Lynch Syndrome

MONDO:0005835 Pathograph 8

Lynch syndrome is an autosomal dominant hereditary cancer predisposition syndrome caused by germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2). It significantly increases the risk of colorectal, endometrial, ovarian, and other cancers, typically presenting at younger ages than sporadic cancers.

0
Mappings
0
Definitions
0
Inheritance
5
Pathophysiology
0
Histopathology
6
Phenotypes
8
Pathograph
5
Genes
4
Treatments
5
Subtypes
0
Differentials
5
Datasets
0
Trials
0
Models
2
Literature
◆

Subtypes

5
MLH1 Mutation
Caused by a mutation in the MLH1 gene, which is involved in DNA mismatch repair.
Show evidence (3 references)
PMID:19466295 SUPPORT
"Lynch syndrome represents 1-7% of all cases of colorectal cancer and is an autosomal-dominant inherited cancer predisposition syndrome caused by germline mutations in deoxyribonucleic acid (DNA) mismatch repair genes"
The literature confirms that Lynch Syndrome is caused by germline mutations in DNA mismatch repair genes, including MLH1.
PMID:38003003 SUPPORT
"MLH1 hypermethylation is an epigenetic alteration in the tumorigenesis of colorectal cancer (CRC) and endometrial cancer (EC), causing gene silencing, and, as a consequence, microsatellite instability."
The literature discusses MLH1 gene involvement in Lynch Syndrome, supporting its significant role.
PMID:34091457 SUPPORT
"Deleterious heterozygous mutation of the MLH1 gene is an important cause of Lynch syndrome (LS), an autosomal dominant cancer caused by functional defects in the DNA mismatch repair (MMR) complex."
The abstract confirms that mutations in the MLH1 gene are a significant cause of Lynch Syndrome.
MSH2 Mutation
Caused by a mutation in the MSH2 gene, which is involved in DNA mismatch repair.
Show evidence (3 references)
PMID:19466295 SUPPORT
"Lynch syndrome represents 1-7% of all cases of colorectal cancer and is an autosomal-dominant inherited cancer predisposition syndrome caused by germline mutations in deoxyribonucleic acid (DNA) mismatch repair genes. Since the discovery of the major human genes with DNA mismatch repair..."
The literature indicates that MSH2 is one of the genes whose mutation is correlated with susceptibility to Lynch syndrome.
PMID:34302852 SUPPORT
"Lynch syndrome (LS) is caused by a pathogenic heterozygous germline variant in one of the DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2."
This directly supports the statement that Lynch syndrome subtypes include those caused by mutations in the MSH2 gene.
PMID:36434153 SUPPORT
"Patients with the heritable cancer disease, Lynch syndrome, carry germline variants in the MLH1, MSH2, MSH6 and PMS2 genes, encoding the central components of the DNA mismatch repair system."
This provides further confirmation that mutations in MSH2 can cause Lynch syndrome, supporting the statement.
MSH6 Mutation
Caused by a mutation in the MSH6 gene, which is involved in DNA mismatch repair.
Show evidence (2 references)
PMID:19466295 SUPPORT
"Since the discovery of the major human genes with DNA mismatch repair function, mutations in five of them have been correlated with susceptibility to Lynch syndrome: mutS homolog 2 (MSH2); mutL homolog 1 (MLH1); mutS homolog 6 (MSH6); postmeiotic segregation increased 2 (PMS2); and postmeiotic..."
The literature confirms that Lynch syndrome can be caused by mutations in the MSH6 gene, which is involved in DNA mismatch repair.
PMID:25430799 SUPPORT
"Sixty-seven (59%) families had mutations in MSH2, 20 (18%) in MSH6, 19 (17%) in MLH1 and 7 (6%) in PMS2."
The study identifies MSH6 as one of the genes with mutations found in Lynch syndrome patients.
PMS2 Mutation
Caused by a mutation in the PMS2 gene, which is involved in DNA mismatch repair.
Show evidence (2 references)
PMID:24027009 SUPPORT
"Lynch syndrome (LS) is a common cancer predisposition caused by an inactivating mutation in one of four DNA mismatch repair (MMR) genes."
Further detail is provided in the study focusing on PMS2 gene's role in MMR and its link to Lynch Syndrome.
PMID:18602922 SUPPORT
"Although the clinical phenotype of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) has been well described, little is known about disease in PMS2 mutation carriers."
The study confirms PMS2 mutations contribute to Lynch Syndrome.
EPCAM Deletion
Caused by a deletion in the EPCAM gene, which can lead to silencing of the MSH2 gene.
Show evidence (3 references)
PMID:23411950 SUPPORT
"Germline mutations of 4 MMR genes, e.g., MLH1, MSH2, MSH6 and PMS2, had been identified as the cause of this disease, however, a novel mechanism, epigenetic inactivation of MSH2 gene due to hypermethylation of promotor region by the deletion of 3'part of epithelial cell adhesion molecule(EPCAM)..."
This reference describes the mechanism by which EPCAM gene deletion causes epigenetic inactivation of the MSH2 gene, supporting the statement.
PMID:30461124 SUPPORT
"Monoallelic deletions of the 3' end of EPCAM that silence the downstream gene, MSH2, cause a form of Lynch syndrome, which is a cancer predisposition syndrome associated with loss of DNA mismatch repair."
This reference further supports the statement by specifying that deletions of the EPCAM gene silence the MSH2 gene, leading to Lynch syndrome.
PMID:23264089 SUPPORT
"These patients carry deletions of the 3' end of the EPCAM gene, including its polyadenylation signal. Due to concomitant transcriptional read-through of EPCAM, the promoter of MSH2 15 kb further downstream becomes inactivated through hypermethylation."
This reference describes the specific mechanism by which EPCAM deletions lead to the inactivation of MSH2, supporting the statement.
📚

References

8
DOI:10.1038/s41431-024-01550-w
Identification of people with Lynch syndrome from those presenting with colorectal cancer in England: baseline analysis of the diagnostic pathway
No top-level findings curated for this source.
DOI:10.1038/s41591-024-02942-7
Nivolumab for mismatch-repair-deficient or hypermutated gynecologic cancers: a phase 2 trial with biomarker analyses
No top-level findings curated for this source.
DOI:10.1200/po.22.00675
Prevalence and Clinical Implications of Mismatch Repair-Proficient Colorectal Cancer in Patients With Lynch Syndrome
No top-level findings curated for this source.
DOI:10.1200/po.23.00332
Microsatellite Instability Is Insufficiently Used as a Biomarker for Lynch Syndrome Testing in Clinical Practice
No top-level findings curated for this source.
DOI:10.32604/or.2025.063951
Lynch syndrome and colorectal cancer: A review of current perspectives in molecular genetics and clinical strategies
No top-level findings curated for this source.
DOI:10.3389/or.2025.1549416
A brief review of Lynch syndrome: understanding the dual cancer risk between endometrial and colorectal cancer
No top-level findings curated for this source.
DOI:10.3390/cancers16050849
Lynch Syndrome: From Multidisciplinary Management to Precision Prevention
No top-level findings curated for this source.
DOI:10.3390/ijms26094394
Deficient Mismatch Repair and Microsatellite Instability in Solid Tumors
No top-level findings curated for this source.
⚙

Pathophysiology

5
DNA Mismatch Repair Deficiency
Mutations in mismatch repair genes lead to an accumulation of DNA replication errors.
colonic epithelial cell link endometrial epithelial cell link
mismatch repair complex link
mismatch repair link ↓ DECREASED DNA-templated DNA replication maintenance of fidelity link ↓ DECREASED DNA damage response link ⚠ ABNORMAL
nucleoplasm link
nucleus link
Show evidence (4 references)
PMID:19466295 SUPPORT
"Lynch syndrome represents 1-7% of all cases of colorectal cancer and is an autosomal-dominant inherited cancer predisposition syndrome caused by germline mutations in deoxyribonucleic acid (DNA) mismatch repair genes."
This reference confirms that Lynch Syndrome involves mutations in mismatch repair genes.
PMID:29233924 SUPPORT
"Many mutations first arise as DNA replication errors. These errors subsequently evade correction by cellular DNA repair, for example, by the well-known DNA mismatch repair (MMR) mechanism."
This supports the notion that DNA mismatch repair is crucial in correcting DNA replication errors, and its deficiency leads to the accumulation of these errors.
PMID:34919656 SUPPORT
"Lynch syndrome (LS, OMIM #120435) is caused by an inherited heterozygous defect in any of the four core DNA mismatch repair (MMR) genes MSH2, MSH6, MLH1 or PMS2..."
Clear evidence linking inherited defects in mismatch repair genes to Lynch Syndrome.
+ 1 more reference
Microsatellite Instability
Defective mismatch repair causes variations in the length of repetitive DNA sequences called microsatellites.
colonic epithelial cell link endometrial epithelial cell link
DNA-templated DNA replication maintenance of fidelity link ↓ DECREASED
colon link endometrium link
Show evidence (4 references)
PMID:25701956 SUPPORT
"Deficient DNA mismatch repair (MMR) results in a strong mutator phenotype known as microsatellite instability (MSI), which is a hallmark of Lynch syndrome-associated cancers."
The snippet confirms that defective mismatch repair causes microsatellite instability, supporting the statement.
PMID:35315099 SUPPORT
"LS tumours are characterised by unique pathogenesis, ultimately resulting in hypermutation, microsatellite instability and high immunogenicity that has significant implications for cancer risk, clinical presentation, treatment and surveillance."
The statement is supported by the evidence that Lynch Syndrome leads to microsatellite instability due to defective mismatch repair.
PMID:31273487 SUPPORT
"Lynch syndrome is a state of mismatch repair deficiency due to a monoallelic abnormality of any mismatch repair genes. The phenotype indicating the mismatch repair deficiency can be frequently shown as a microsatellite instability in tumors."
This reference supports the statement by linking mismatch repair deficiency and microsatellite instability in Lynch Syndrome.
+ 1 more reference
Accelerated Tumor Development
The accumulation of mutations in key genes leads to an increased risk of developing certain cancers at an earlier age.
colonic epithelial cell link endometrial epithelial cell link
cell population proliferation link ↑ INCREASED
colon link endometrium link
Show evidence (2 references)
PMID:37478804 SUPPORT
"Lynch Syndrome (LS) is one of the most common hereditary cancer syndromes, and is caused by mutations in one of the four DNA mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6 and PMS2."
This further supports the fact that accumulation of mutations in key genes (MMR genes) in Lynch Syndrome contributes to an increased risk of developing certain cancers.
PMID:23604856 SUPPORT
"Lynch Syndrome, or hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant cancer predisposition syndrome caused by inactivating mutations in DNA mismatch repair genes."
This supports the idea that the mechanism of Lynch Syndrome involves the accumulation of mutations in key genes leading to cancer.
Neoantigen Generation and Immune Activation
Frameshift mutations in coding repeats generate tumor neoantigens that activate tumor-infiltrating lymphocytes and create an immunogenic tumor microenvironment.
CD8-positive, alpha-beta T cell link
antigen processing and presentation of peptide antigen via MHC class I link ↑ INCREASED type I interferon-mediated signaling pathway link ↑ INCREASED T cell mediated cytotoxicity directed against tumor cell target link ↑ INCREASED
colon link endometrium link
Show evidence (2 references)
PMID:34630437 SUPPORT
"We and others have characterized a subset of MSI-H associated highly recurrent frameshift mutations that yield shared immunogenic neoantigens."
This directly supports neoantigen generation from recurrent frameshift events in mismatch repair-deficient, MSI-high tumors seen in Lynch syndrome.
PMID:35315099 SUPPORT
"LS tumours are characterised by unique pathogenesis, ultimately resulting in hypermutation, microsatellite instability and high immunogenicity that has significant implications for cancer risk, clinical presentation, treatment and surveillance."
This supports the immunogenic tumor microenvironment and immune activation component of this mechanism.
Immune Checkpoint Blockade Sensitivity
Lynch-associated dMMR/MSI tumors with high neoantigen burden are enriched for anti-tumor T-cell activity and show strong responses to PD-1 blockade.
T cell mediated cytotoxicity directed against tumor cell target link ↑ INCREASED
Show evidence (2 references)
PMID:37625240 SUPPORT
"PD-1 inhibitors are highly effective for dMMR and MSI-H LS CRCs, but not for pMMR or MSS LS CRCs or mucinous/signet-ring cell CRC."
This human clinical observation supports mechanistic sensitivity of dMMR/MSI Lynch tumors to immune checkpoint blockade.
PMID:37845474 PARTIAL
"Metastatic and localized mismatch repair-deficient (dMMR) tumors are exquisitely sensitive to immune checkpoint blockade (ICB)."
This supports high treatment sensitivity in dMMR states while also indicating that surveillance remains necessary.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Referential integrity issues (2):
  • Target 'Metastatic Disease' (from 'Colorectal Cancer') not found in named elements
  • Target 'Bowel Obstruction' (from 'Colorectal Cancer') not found in named elements
Pathograph: causal mechanism network for Lynch Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Digestive 1
Stomach Cancer FREQUENT Stomach cancer (HP:0012126)
Show evidence (2 references)
PMID:31319185 SUPPORT
"Lynch syndrome is the most common inherited cause of gastrointestinal cancer and increases risk for a variety of malignancies, including gastric cancer."
The reference supports the increased frequency of stomach (gastric) cancer as a phenotype of Lynch Syndrome.
PMID:27546846 PARTIAL
"Approximately 5% arise from germline mutations in genes associated with cancer predisposition."
While this provides general context about hereditary gastrointestinal cancers, it does not specify Lynch Syndrome or stomach cancer.
Other 5
Colorectal Cancer VERY_FREQUENT colorectal cancer (MONDO:0005575)
Sequelae: Metastatic Disease Bowel Obstruction
Show evidence (9 references)
PMID:37088804 PARTIAL
"Some patients with Lynch syndrome (LS) have extreme phenotypes, i.e. cancer before the recommended screening age, or cancer for which there are no screening guidelines."
While this study mentions patients with Lynch syndrome having early-onset cancer, it does not specify whether it includes colorectal cancer or not. It partially supports the statement on phenotypes.
PMID:16136388 SUPPORT
"The major aim of surveillance in Lynch syndrome is to diagnose malignant or premalignant lesions at the asymptomatic stage by regular checkups, particularly in the large bowel."
Supports the high frequency of colorectal cancer diagnosis in Lynch syndrome as a major phenotype.
PMID:29071502 SUPPORT
"Lynch syndrome is the hereditary disorder that most frequently predisposes to colorectal cancer..."
Affirms that Lynch syndrome frequently predisposes to colorectal cancer, supporting a high-frequency diagnostic.
+ 6 more references
Endometrial Cancer VERY_FREQUENT endometrial cancer (MONDO:0011962)
Show evidence (4 references)
PMID:28376523 SUPPORT
"The clinical characteristics of Lynch-associated endometrial cancer and screening and risk-reducing strategies also are described."
The article discusses Lynch syndrome and its association with endometrial cancer, supporting the statement.
PMID:23681793 SUPPORT
"Carriers of MMR defects have a strongly increased risk of developing CRC and endometrial cancer."
The article states that Lynch syndrome carriers have a strongly increased risk of developing endometrial cancer.
PMID:29071502 SUPPORT
"Lynch syndrome is the hereditary disorder that most frequently predisposes to colorectal cancer as well as predisposing to a number of extracolonic cancers, most prominently endometrial cancer."
The review confirms that Lynch syndrome prominently predisposes individuals to endometrial cancer.
+ 1 more reference
Urinary Tract Cancer OCCASIONAL renal pelvis/ureter urothelial carcinoma (MONDO:0020654)
Transitional cell carcinoma of the ureter or renal pelvis
Show evidence (5 references)
PMID:31615790 SUPPORT
"Lynch syndrome confers markedly increased risks of various malignancies, including urinary tract cancers (UTC; renal pelvis, ureter, bladder, and possibly kidney cancers)."
This large cohort supports urinary tract cancer as a recognized Lynch-associated malignancy and informs clinical risk stratification.
PMID:21419447 SUPPORT
"Patients with Lynch syndrome are much more likely to have generally rare upper urinary tract urothelial carcinoma but not bladder urothelial carcinoma."
The literature supports the occurrence of upper urinary tract cancer (urothelial carcinoma) in patients with Lynch syndrome, which includes transitional cell carcinoma of the ureter or renal pelvis.
PMID:34798988 SUPPORT
"Lynch syndrome (LS) is a common form of inherited cancer susceptibility, which predisposes to colorectal cancer (CRC) along with a wide array of other extracolonic malignancies, including other gastrointestinal cancers, cancers of the gynecologic and genitourinary tracts, and other organ sites."
The literature confirms that Lynch syndrome is associated with cancers of the genitourinary tract, which includes urinary tract cancer.
+ 2 more references
Ovarian Cancer OCCASIONAL ovarian carcinoma (MONDO:0005140)
Show evidence (1 reference)
PMID:35435397 SUPPORT
"There is an increased predisposition to cancers in the endometrium, colon, stomach, ovary, uterus, skin, kidney, and brain in patients of Lynch syndrome."
This reference supports the association between Lynch Syndrome and ovarian cancer.
Sebaceous Adenomas OCCASIONAL sebaceous adenoma (MONDO:0002375)
Muir-Torre variant of Lynch syndrome
Show evidence (3 references)
PMID:25427047 SUPPORT
"Muir-Torre syndrome (MTS) is a rare autosomal-dominant genodermatosis characterized by sebaceous neoplasms and one or more visceral malignancies. Sebaceous tumors include sebaceous adenoma and carcinoma, which may be solitary or multiple."
The reference confirms that sebaceous adenomas are a part of the dermatologic manifestations in the Muir-Torre variant of Lynch syndrome.
PMID:34023105 SUPPORT
"Sebaceous adenoma, sebaceoma, and a subset of cutaneous SC are frequently associated with defective DNA mismatch repair resulting from mutations in MLH1, MSH2, or MSH6. These tumors can be sporadic or associated with Muir-Torre syndrome."
The reference supports the association of sebaceous adenomas with Lynch syndrome, particularly in the context of Muir-Torre syndrome.
PMID:36418753 SUPPORT
"The main skin lesions were: Sebaceous adenomas (43%), sebaceous carcinomas (27%), keratoacanthomas (16%), sebaceomas (13%), squamous cell carcinomas (23%), and basal cell carcinomas (10%)."
This systematic review confirms sebaceous adenoma as a common cutaneous Lynch-associated manifestation.
🧬

Genetic Associations

5
MLH1 (Germline Mutation)
Autosomal Dominant
Show evidence (2 references)
PMID:28038733 SUPPORT
"Lynch syndrome is due to germline mutations in mismatch repair genes: MLH1, MSH2, MSH6 and PMS2."
The reference directly indicates that Lynch syndrome is caused by germline mutations in the MLH1 gene among others.
PMID:26886015 SUPPORT
"Constitutional epimutation of the DNA mismatch repair gene, MLH1, represents a minor cause of Lynch syndrome."
While the term 'epimutation' is used, it is within the context of the DNA mismatch repair gene MLH1 being a cause of Lynch syndrome.
MSH2 (Germline Mutation)
Show evidence (2 references)
PMID:29345684 PARTIAL
"Our data demonstrate that two LS genes, MSH6 and PMS2, are associated with an increased risk for breast cancer..."
While the MSH2 gene is mentioned, the research did not find a statistically significant association between MSH2 and breast cancer risk.
PMID:25430799 SUPPORT
"Sixty-seven (59%) families had mutations in MSH2..."
This study reports a significant proportion of Lynch syndrome families with mutations in MSH2.
MSH6 (Germline Mutation)
Show evidence (5 references)
PMID:20028993 SUPPORT
"Germline mutations in MSH6 account for 10%-20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations."
The study explicitly states that germline mutations in MSH6 are associated with Lynch Syndrome cancers.
PMID:28038733 SUPPORT
"Lynch syndrome is due to germline mutations in mismatch repair genes: MLH1, MSH2, MSH6 and PMS2."
The study identifies germline mutations in MSH6 as a cause of Lynch Syndrome.
PMID:33516942 SUPPORT
"A MSH6 3'UTR variant (c.*23_26dup) was found in 13 unrelated families consulted for Lynch/Muir-Torre Syndrome."
The study highlights that a specific variant of MSH6 is associated with families affected by Lynch Syndrome.
+ 2 more references
PMS2 (Germline Mutation)
Show evidence (4 references)
PMID:18602922 SUPPORT
"PMS2 mutations contribute significantly to Lynch syndrome, but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes."
This study confirms that germline mutations in PMS2 are associated with Lynch syndrome.
PMID:24027009 SUPPORT
"Lynch syndrome (LS) is a common cancer predisposition caused by an inactivating mutation in one of four DNA mismatch repair (MMR) genes. Frequently a variant of uncertain significance (VUS), rather than an obviously pathogenic mutation, is identified in one of these genes. The inability to..."
The study discusses analyzing VUS in the MMR gene PMS2 for functional activity, indicating the association of PMS2 germline mutations with Lynch syndrome.
PMID:37072247 SUPPORT
"As a result of our analysis, we managed to identify a mutation in the PMS2 gene in one patient's breast tumor tissue. The presence of this mutation indicates that the resulting cancer may be a consequence of LS."
This study identifies a mutation of the PMS2 gene associated with Lynch syndrome, supporting the genetic association.
+ 1 more reference
EPCAM (Germline Mutation)
Show evidence (3 references)
PMID:23411950 SUPPORT
"Germline mutations of 4 MMR genes, e.g., MLH1, MSH2, MSH6 and PMS2, had been identified as the cause of this disease, however, a novel mechanism, epigenetic inactivation of MSH2 gene due to hypermethylation of promotor region by the deletion of 3'part of epithelial cell adhesion molecule(EPCAM)..."
PMID:30461124 SUPPORT
"Monoallelic deletions of the 3' end of EPCAM that silence the downstream gene, MSH2, cause a form of Lynch syndrome, which is a cancer predisposition syndrome associated with loss of DNA mismatch repair."
PMID:37088804 SUPPORT
"Four EO cases stood out: two with POLE/POLD1 variants in the key exonuclease domain, one with a BMPR1A duplication and one with an EPCAM deletion."
EPCAM deletion is mentioned as one of the variants related to Lynch Syndrome.
💊

Treatments

4
Increased Cancer Surveillance
Regular colonoscopies, endometrial biopsies, and other screening tests to detect cancers early.
Show evidence (5 references)
PMID:23176623 SUPPORT
"Some periodic screening strategies, such as colonoscopy, reduce the incidence and mortality of Lynch syndrome."
Regular colonoscopies are highlighted as a beneficial screening strategy for Lynch Syndrome.
PMID:31629885 SUPPORT
"...offering the FDRs with Lynch syndrome biennial colonoscopy surveillance was cost-effective..."
The study emphasizes the importance of regular colonoscopy surveillance for those with Lynch syndrome.
PMID:34698909 SUPPORT
"Lynch syndrome (LS) is the most common cause of hereditary colorectal cancer and is associated with an increased lifetime risk of gastric and duodenal cancers of 8-16% and 7%, respectively; therefore, we aim to describe an esophagogastroduodenoscopy (EGD) surveillance program..."
Endoscopies like EGD are implemented for cancer surveillance in LS patients, corroborating the need for ongoing screening tests.
+ 2 more references
Prophylactic Surgery
Action: surgical procedure MAXO:0000004
Preventive removal of the colon, uterus, or ovaries may be considered in some cases.
Show evidence (4 references)
PMID:21287222 SUPPORT
"Patients who are gene mutation carriers should receive counseling about colectomy, and if women, prophylactic hysterectomy and bilateral oophorectomy."
The literature mentions counseling carriers about colectomy and prophylactic hysterectomy with bilateral oophorectomy, supporting that preventive removal of the colon, uterus, or ovaries may be considered.
PMID:24495259 SUPPORT
"Prophylactic hysterectomy with bilateral salpingo-oophorectomy is being increasingly undertaken in patients with Lynch syndrome (LS)."
The literature indicates that prophylactic hysterectomy with bilateral salpingo-oophorectomy is a preventive measure undertaken in Lynch syndrome patients.
PMID:31554630 SUPPORT
"for women with Lynch syndrome, the risks for gynecologic cancers pose an equal or greater risk than colorectal cancer."
The literature outlines the significant risk of gynecologic cancers in women with Lynch syndrome, supporting the consideration of prophylactic surgery.
+ 1 more reference
Chemoprevention
Action: pharmacotherapy MAXO:0000058
Agent: acetylsalicylic acid ↗
Aspirin or other NSAIDs may reduce the risk of colorectal cancer in Lynch syndrome patients.
Show evidence (4 references)
PMID:35328014 SUPPORT
"Nonsteroidal anti-inflammatory drugs and, in particular, aspirin use, has been associated with reduced CRC risk in several studies..."
This study affirms that aspirin and other NSAIDs have been linked to a reduced risk of colorectal cancer in Lynch syndrome patients.
PMID:11854387 PARTIAL
"Numerous experimental, epidemiologic, and clinical studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs), particularly the highly selective cyclooxygenase (COX)-2 inhibitors, have promise as anticancer agents..."
The study indicates a potential for NSAIDs in cancer prevention, including colorectal cancer, but notes that unresolved questions about safety and efficacy limit clinical application.
PMID:36202092 SUPPORT
"...multiple pharmacological, clinical, and epidemiologic studies suggest that aspirin can prevent certain cancers..."
This study supports the role of aspirin in cancer prevention, including colorectal cancer, though mentions variable effects depending on the tissue and disease context.
+ 1 more reference
Targeted Therapies
Action: pharmacotherapy MAXO:0000058
Immunotherapies like checkpoint inhibitors may be effective for treating some Lynch syndrome-related cancers.
Show evidence (4 references)
PMID:37625240 SUPPORT
"PD-1 inhibitors are highly effective for dMMR and MSI-H LS CRCs, but not for pMMR or MSS LS CRCs or mucinous/signet-ring cell CRC."
This study demonstrates the efficacy of PD-1 inhibitors, a type of immune checkpoint inhibitor, for treating Lynch syndrome (LS) patients with colorectal cancers characterized by deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H).
PMID:34224739 SUPPORT Model Organism
"We identified 4 shared FSP neoantigens ... Using VCMsh2 mice, which have a conditional knockout of Msh2 in the intestinal tract and develop intestinal cancer, we showed vaccination with a combination of only 4 FSPs significantly increased FSP-specific adaptive immunity, reduced intestinal tumor..."
This study indicates that immunotherapies, specifically FSP neoantigen vaccines, can be effective in reducing the tumor burden and improving survival in Lynch syndrome mouse models.
PMID:30027543 SUPPORT
"Immunotherapies are an active field of research for MSI cancers and their potential use for cancer therapy for both sporadic and LS MSI cancers is discussed."
This reference discusses ongoing research into immunotherapies for MSI cancers, including those associated with Lynch syndrome.
+ 1 more reference
🌍

Environmental Factors

1
Not Applicable
Lynch syndrome is primarily caused by inherited genetic mutations.
Show evidence (2 references)
PMID:29345160 REFUTE
"Environmental factors that play a role in the urothelial carcinogenesis have been well characterized. Current research is continuously exploring potential heritable forms of bladder cancer. Lynch syndrome is a well-known inheritable disease that increases the risk for a variety of cancers,..."
Lynch syndrome is described as an inherited disease, implying a genetic rather than environmental origin.
PMID:31296810 REFUTE
"Lynch syndrome is caused by germline pathogenic variants in any of 4 DNA mismatch repair(MMR)genes MLH1, MSH2, MSH6 or PMS2 and rarely in the non-MMR gene EPCAM, in which deletion of its last exon induce epigenetic silencing of MSH2."
This indicates that Lynch syndrome is caused by genetic mutations, not by environmental factors.
🔬

Biochemical Markers

2
Microsatellite Instability Testing
Show evidence (4 references)
PMID:21970482 SUPPORT
"About 15% of colorectal cancers are characterized by genomic microsatellite instability, and of these, about 1 in 5 (2%-4% overall) are due to Lynch syndrome..."
The reference discusses the correlation between Lynch syndrome and microsatellite instability in colorectal cancers, supporting that Lynch Syndrome can be biochemically identified via microsatellite instability testing.
PMID:34611695 SUPPORT
"The most important tumor characteristic of Lynch syndrome (LS) is microsatellite instability (MSI)."
This reference explicitly states that microsatellite instability is a critical characteristic of Lynch syndrome, supporting the statement.
PMID:38466935 SUPPORT
"Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline mutations in DNA mismatch repair genes, which lead to high microsatellite instability..."
The high microsatellite instability mentioned in this literature underscores the biochemical connection between Lynch syndrome and microsatellite instability testing.
+ 1 more reference
Immunohistochemistry
Show evidence (3 references)
PMID:22067175 SUPPORT
"DNA mismatch repair immunohistochemistry on tumor tissue is a simple, readily available, and cost-effective method of identifying patients with Lynch syndrome."
The study explains that DNA mismatch repair immunohistochemistry is used for identifying Lynch syndrome, supporting the idea that biochemical tests involving immunohistochemistry can confirm the presence of absent mismatch repair proteins in tumors.
PMID:19817892 SUPPORT
"In Lynch syndrome adenomas, loss of mismatch repair proteins is related to an enhanced lymphocytic response."
The study directly correlates the loss of mismatch repair proteins with Lynch syndrome, supporting the use of immunohistochemistry to detect these biochemical changes.
PMID:24333619 SUPPORT
"Lynch syndrome is caused by germline mutations in the mismatch repair (MMR) genes."
This supports the statement by linking Lynch syndrome to mutations in mismatch repair genes, which can be identified using immunohistochemistry.
📊

Related Datasets

5
Gene expression Classification of Colon Cancer defines six molecular subtypes with distinct clinical, molecular and survival characteristics [Expression] geo:GSE39582
Large French multicenter cohort (Cartes d'Identité des Tumeurs program) with 566 colon tumor samples and 19 non-tumoral colorectal mucosa samples (585 total) including MSI status annotation. Contains 71 MSI-high and 439 MSS samples, useful for studying Lynch syndrome-associated molecular signatures.
human MICROARRAY n=585 Affymetrix Human Genome U133 Plus 2.0 Array
colon tumor tissue
Conditions: MSI-high colon cancer MSS colon cancer non-tumoral colorectal mucosa
PMID:23700391
Identifies six molecular subtypes with distinct survival outcomes. MSI status allows identification of Lynch-like tumors and study of immune infiltration patterns.
Show evidence (1 reference)
PMID:23700391 SUPPORT
"566 samples fulfilled RNA quality requirements. Unsupervised consensus hierarchical clustering applied to gene expression data from a discovery subset of 443 CC samples identified six molecular subtypes."
This supports the cohort composition and molecular subtype characterization captured in this dataset entry.
Metastasis Gene Expression Profile Predicts Recurrence and Death in Colon Cancer Patients (Moffitt Samples) geo:GSE17536
Independent validation cohort of 177 colon cancer samples from Moffitt Cancer Center with clinical outcome data including metastasis risk and survival information.
human MICROARRAY n=177
colon tumor tissue
Conditions: colon cancer (various stages)
PMID:19914252
Used with GSE39582 for validation of molecular classifiers. Contains stage information useful for prognostic analysis
Show evidence (1 reference)
PMID:19914252 SUPPORT
"This phase 1, exploratory biomarker study used 55 patients with colorectal cancer from Vanderbilt Medical Center (VMC) as the training dataset and 177 patients from the Moffitt Cancer Center as the independent dataset."
This directly supports the Moffitt cohort sample count and study context represented in this dataset entry.
Immune Profiling of Premalignant Lesions in Patients with Lynch Syndrome geo:GSE106500
RNA-seq cohort of colorectal adenomas from Lynch syndrome patients, with comparator familial adenomatous polyposis adenomas, used for transcriptomic immune profiling of premalignant lesions.
human BULK RNA SEQ n=24 Illumina HiSeq 2000
colorectal adenoma tissue
Conditions: Lynch syndrome colorectal adenoma familial adenomatous polyposis colorectal adenoma
PMID:29710228
Focuses on early lesion immune activation and checkpoint biology in LS, useful for mechanistic chemoprevention and interception studies.
Show evidence (1 reference)
PMID:29710228 SUPPORT
"Whole-genome transcriptomic analysis using next-generation sequencing was performed in colorectal polyps and carcinomas of patients with LS."
This directly supports transcriptomic sequencing in Lynch syndrome colorectal premalignant/tumor lesions relevant to this GEO cohort.
Molecular subtype classification of urothelial carcinoma in Lynch syndrome geo:GSE104922
Microarray cohort of Lynch syndrome-associated urothelial cancers from bladder and upper urinary tract, profiled for molecular subtype mapping, MSI status, and clinicopathologic associations.
human MICROARRAY n=41 Affymetrix Human Gene 1.0 ST Array
urinary bladder tumor tissue upper urinary tract tumor tissue
Conditions: Lynch syndrome urothelial carcinoma upper urinary tract urothelial carcinoma bladder urothelial carcinoma
PMID:29791078
Enables analysis of urinary tract phenotypes in LS and comparison to sporadic urothelial molecular subtypes.
Show evidence (1 reference)
PMID:29791078 SUPPORT
"Whole-genome mRNA expression profiles of 41 tumors and immunohistochemical stainings against FGFR3, KRT5, CCNB1, RB1, and CDKN2A (p16) of 37 tumors from patients with Lynch syndrome were generated."
This supports both the cohort scale and molecular profiling design represented in this Lynch-associated urothelial dataset.
Distinct tumorigenic pathways within hereditary nonpolyposis colorectal cancer geo:GSE36335
FFPE colorectal cancer expression cohort spanning Lynch syndrome, familial colorectal cancer type X (FCCTX), and sporadic CRC, designed to identify hereditary pathway-level differences.
human MICROARRAY n=132 Illumina HumanHT-12 WG-DASL V4.0 R2...
colorectal carcinoma tissue
Conditions: Lynch syndrome colorectal cancer familial colorectal cancer type X sporadic colorectal cancer
PMID:23951239
Useful for distinguishing LS-specific transcriptional programs from FCCTX and sporadic CRC backgrounds.
Show evidence (1 reference)
PMID:23951239 SUPPORT
"The 18 k whole-genome c-DNA-mediated annealing, selection, extension, and ligation (WG-DASL) assay was applied to 123 colorectal cancers, including 39 Lynch syndrome tumors and 37 FCCTX tumors."
This supports the hereditary colorectal expression profiling framework and LS-relevant tumor subset captured in this GEO series.
📚

Literature Summaries

2
Disorder ▸

Disorder

  • Name: Lynch Syndrome
  • Category:
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 115

Key Pathophysiology Nodes

  • DNA Mismatch Repair Deficiency
  • Microsatellite Instability
  • Accelerated Tumor Development
  • Neoantigen Generation and Immune Activation
  • Immune Checkpoint Blockade Sensitivity
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1038/s41431-024-01550-w
  • DOI:10.1038/s41591-024-02942-7
  • DOI:10.1200/po.22.00675
  • DOI:10.1200/po.23.00332
  • DOI:10.32604/or.2025.063951
  • DOI:10.3389/or.2025.1549416
  • DOI:10.3390/cancers16050849
  • DOI:10.3390/ijms26094394
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 32 citations 2025-12-15T09:12:09.059093

Disease Pathophysiology Research Report

Target Disease

  • Disease Name: Lynch Syndrome (LS; hereditary nonpolyposis colorectal cancer)
  • MONDO ID: [not definitively confirmed here]
  • Category: Hereditary cancer predisposition syndrome (DNA mismatch repair deficiency)

Research Objectives: Pathophysiology of Lynch Syndrome

Element Representative items (IDs where requested) Real-world implementations Key 2023–24 statistics Evidence
Core pathophysiology Germline heterozygous MMR defects → somatic "second hit" → MMR deficiency (dMMR) → microsatellite instability (MSI), hypermutation, frameshift neoantigens; cGAS–STING → type I IFN activation (GO:0006281; GO:0060337) Tumor IHC (MLH1/MSH2/MSH6/PMS2) and MSI testing; germline multigene panels; somatic MLH1 methylation/BRAF to triage LS explains ≈3% of CRC; dMMR produces hypermutated/MSI-H phenotype linked to neoantigens and immune activation (sowter2024identifyingcandidatesfor pages 45-48, buono2024lynchsyndromefrom pages 3-5, gomezmolina2025lynchsyndromeand pages 2-3)
Key molecular players HGNC symbols: MLH1, MSH2, MSH6, PMS2, EPCAM; CHEBI:15365 (acetylsalicylic acid = aspirin) Diagnostic: four-stain IHC; NGS panels for germline/somatic; functional assays for VUS Gene-specific penetrance: MLH1/MSH2 higher CRC risk; MSH6/PMS2 lower but significant; PMS2 carriage estimates (population) noted in recent series (pallatt2025abriefreview pages 3-5, gomezmolina2025lynchsyndromeand pages 2-3)
Disrupted GO biological processes DNA repair (GO:0006281); response to DNA damage (GO:0006974); type I interferon signaling (GO:0060337); immune response (GO:0006955) Mechanistic rationale for PD-1/PD-L1 therapy and trials of STING/ATR modulators dMMR/MSI-H tumours have high TMB and elevated neoantigen burden; immunotherapy ORR in dMMR cohorts reported in the literature in the ~40–60% range (awosika2025deficientmismatchrepair pages 3-4, buono2024lynchsyndromefrom pages 1-2, sowter2024identifyingcandidatesfor pages 45-48)
Cellular components (GO CC) Nucleus (GO:0005634); nucleoplasm (GO:0005654); cytosol (GO:0005829); endoplasmic reticulum (STING localization) (GO:0005783) IHC staining patterns (loss/retention of MMR proteins) guide downstream testing MMR protein loss by IHC (sensitivity ~83–92%; specificity ~89% reported for tumor screening workflows) (sowter2024identifyingcandidatesfor pages 45-48, gomezmolina2025lynchsyndromeand pages 2-3)
Phenotypes (HPO) Colorectal carcinoma; Endometrial carcinoma; multiple primary tumours; early-onset cancers (HPO terms used in KBs) Clinical surveillance (colonoscopy, gynaecologic screening), risk-reducing surgery options Lifetime risks vary by gene (examples: MLH1/MSH2 substantially elevated CRC/EC risk; MSH6/PMS2 more variable) (buono2024lynchsyndromefrom pages 3-5, gomezmolina2025lynchsyndromeand pages 2-3)
Cell types (CL) Colonic/intestinal epithelial cells (colonocytes), endometrial epithelial cells, tumour-infiltrating CD8+ T cells Studies of tumour microenvironment, vaccine targets (frameshift peptides) and biomarker assays dMMR tumours characteristically show brisk lymphoid infiltration (TILs) and inflammatory signatures (awosika2025deficientmismatchrepair pages 3-4, buono2024lynchsyndromefrom pages 3-5)
Anatomical locations (UBERON) Colon (UBERON:0001155), endometrium, ovary, stomach, urinary tract, pancreas (LS tumour spectrum) Site-specific surveillance programs and expanded universal screening in CRC/EC LS contributes to increased lifetime risk across these organs; percent contribution of LS varies by tumour type (e.g., ~3% CRC, higher proportions among dMMR cases) (buono2024lynchsyndromefrom pages 1-2, gomezmolina2025lynchsyndromeand pages 2-3)
Real-world implementations Universal tumor screening (IHC/MSI), reflex MLH1 methylation and BRAF testing to distinguish sporadic MLH1-silenced tumours; germline testing; PD-1 inhibitors for dMMR/MSI-H cancers; aspirin chemoprevention (CAPP trials) and experimental FSP vaccines Health-system pathways: tumor -> methylation/BRAF -> germline referral; ICI approved for dMMR/MSI-H across tumour types Implementation gaps reported (underdiagnosis / incomplete testing uptake); established therapeutic benefit of checkpoint blockade in dMMR tumours (sowter2024identifyingcandidatesfor pages 45-48, buono2024lynchsyndromefrom pages 3-5, buono2024lynchsyndromefrom pages 1-2)
Key 2023–24 statistics Population prevalence estimates: LS carrier frequency reported in range ~1:300–1:1000 (variable by cohort); LS accounts for ~3% of CRC; IHC/MSI testing sensitivity/specificity and immunotherapy ORR ranges Examples: proportion of CRCs screened and referral gaps documented; immunotherapy response rates in dMMR cohorts reported in recent trials/reviews Screening and surveillance modify observed penetrance; actionable ICI response rates commonly reported ~40–60% in dMMR cohorts; aspirin/resistant starch trials ongoing for prevention (sowter2024identifyingcandidatesfor pages 45-48, awosika2025deficientmismatchrepair pages 3-4, buono2024lynchsyndromefrom pages 1-2)

Table: Compact, evidence-linked table summarizing core pathophysiology, molecular players (HGNC/CHEBI), disrupted GO processes and cellular components, phenotypes, cell types, anatomical sites, implementations and key 2023–24 statistics for Lynch syndrome; intended for embedding in a knowledge-base entry. Evidence column lists the context IDs supporting each row.

"A germline hit plus somatic second alteration leads to dMMR, producing accelerated carcinogenesis, high frameshift mutation rates and MSI." (buono2024lynchsyndromefrom pages 3-5)

"Only 44% of CRCs were screened for dMMR." (mcronald2024identificationofpeople pages 1-2)

"Only 1.3% of CRC patients had a germline MMR genetic test performed." (mcronald2024identificationofpeople pages 1-2)

"Only 22.73% (45/198 MSI-high cases) underwent germline testing; ... MLH1 methylation testing is 'barely ever requested' in clinical practice." (papadopoulou2024microsatelliteinstabilityis pages 1-2)

"The ORR was 58.8% and the PFS24 rate was 64.7%." (friedman2024nivolumabformismatchrepairdeficient pages 1-2)

"Hereditary syndromes associated with EC include Lynch syndrome." (ranganathan2023prevalenceandclinical pages 10-11)

Blockquote: Direct, citable quotes highlighting core mechanism (germline + second hit → dMMR/MSI), major implementation gaps in tumor/germline testing in England and practice, limited use of MLH1 methylation reflex testing, and immunotherapy outcomes (nivolumab) in dMMR gynecologic cancers.

1) Core Pathophysiology: Key concepts and definitions

  • Definition and inheritance: Lynch syndrome is an autosomal-dominant cancer predisposition syndrome caused by germline pathogenic variants in DNA mismatch repair (MMR) genes—MLH1, MSH2, MSH6, PMS2—or 3′ EPCAM deletions that epigenetically silence MSH2. Tumorigenesis follows a “two-hit” model: the germline hit plus a somatic second hit inactivates the remaining allele, leading to mismatch repair deficiency (dMMR) and microsatellite instability (MSI) with a hypermutated phenotype (reviewed in 2024–2025 sources). URL: https://doi.org/10.3390/cancers16050849; https://doi.org/10.32604/or.2025.063951 (buono2024lynchsyndromefrom pages 3-5, gomezmolina2025lynchsyndromeand pages 1-2, gomezmolina2025lynchsyndromeand pages 2-3)
  • Molecular mechanism: Loss of MMR function impairs recognition and repair of base–base mismatches and insertion/deletion loops (MutSα: MSH2/MSH6; MutSβ: MSH2/MSH3; MutLα: MLH1/PMS2), driving genome-wide MSI and accumulation of frameshift mutations in coding repeats. These frameshifts generate neoantigens and underlie the immunogenic tumor microenvironment typical of dMMR/MSI-H cancers. URL: https://doi.org/10.3390/ijms26094394 (awosika2025deficientmismatchrepair pages 3-4)
  • Immune consequences: Hypermutation and frameshift neoantigens are associated with brisk lymphocytic infiltration and clinical sensitivity to PD-1 blockade across dMMR/MSI-H tumors. URL: https://doi.org/10.3390/ijms26094394; https://doi.org/10.3390/cancers16050849 (awosika2025deficientmismatchrepair pages 3-4, buono2024lynchsyndromefrom pages 3-5)
  • Screening paradigm (definition in practice): Tumor-based universal screening for dMMR/MSI by IHC and/or MSI testing with reflex MLH1 promoter methylation and BRAF V600E testing distinguishes sporadic MLH1-hypermethylated tumors from LS, and positive screens prompt germline testing. URL: (overview) https://doi.org/10.3390/cancers16050849; implementation data: https://doi.org/10.1038/s41431-024-01550-w; https://doi.org/10.1200/po.23.00332 (buono2024lynchsyndromefrom pages 3-5, mcronald2024identificationofpeople pages 1-2, papadopoulou2024microsatelliteinstabilityis pages 1-2)

Latest mechanistic understanding (2023–2024 emphasis): - dMMR/MSI produces high tumor mutational burden and frameshift peptide neoantigens; the dMMR microenvironment is often “hot,” with effector T-cell infiltration, contributing to responsiveness to checkpoint inhibitors (PD-1/PD-L1). URL: https://doi.org/10.3390/ijms26094394 (awosika2025deficientmismatchrepair pages 3-4) - Early MSI/dMMR crypts in normal mucosa are reported as potential occult precursors in LS, supporting accelerated adenoma-to-carcinoma progression in some carriers. URL: https://doi.org/10.3390/cancers16050849 (buono2024lynchsyndromefrom pages 3-5)

2) Key molecular players

  • Genes/Proteins (HGNC): MLH1, MSH2, MSH6, PMS2, EPCAM (EPCAM 3′ deletions cause MSH2 silencing). URL: https://doi.org/10.3390/cancers16050849; https://doi.org/10.32604/or.2025.063951 (buono2024lynchsyndromefrom pages 3-5, gomezmolina2025lynchsyndromeand pages 1-2, gomezmolina2025lynchsyndromeand pages 2-3)
  • Chemical entities (CHEBI): Acetylsalicylic acid (aspirin; CHEBI:15365) has emerging chemopreventive evidence in LS; resistant starch is also under study. URL: https://doi.org/10.3390/cancers16050849 (buono2024lynchsyndromefrom pages 3-5)
  • Cell types (CL): Colonic/intestinal epithelium and endometrial epithelium are primary tissues of origin; tumor-infiltrating lymphocytes (notably CD8+ T cells) typify dMMR/MSI-H tumors. URL: https://doi.org/10.3390/ijms26094394; https://doi.org/10.3390/cancers16050849 (awosika2025deficientmismatchrepair pages 3-4, buono2024lynchsyndromefrom pages 3-5)
  • Anatomical locations (UBERON): Colon and rectum, endometrium, ovary, stomach, urinary tract, and other LS-spectrum sites. URL: https://doi.org/10.3390/cancers16050849 (buono2024lynchsyndromefrom pages 3-5)

3) Biological processes (GO terms) dysregulated

  • DNA repair (GO:0006281), mismatch repair (component of GO:0006281), response to DNA damage stimulus (GO:0006974). URL: https://doi.org/10.3390/ijms26094394 (awosika2025deficientmismatchrepair pages 3-4)
  • Antigen processing/immune response (GO:0006955) and Type I interferon signaling (GO:0060337) consistent with immunogenic dMMR/MSI-H microenvironments. URL: https://doi.org/10.3390/ijms26094394 (awosika2025deficientmismatchrepair pages 3-4)

4) Cellular components

  • Nucleus/nucleoplasm where MMR operates (GO:0005634; GO:0005654) and cytosol (GO:0005829); checkpoint signaling impacts antigen presentation pathways. URL: https://doi.org/10.3390/ijms26094394 (awosika2025deficientmismatchrepair pages 3-4)
  • Practical laboratory components: Loss of MLH1/MSH2/MSH6/PMS2 staining by IHC supports dMMR designation; IHC sensitivity ~83–92% and specificity ~89% are reported in screening workflows. URL: (overview) [Sowter 2024, assay performance described] (sowter2024identifyingcandidatesfor pages 45-48)

5) Disease progression (sequence of events)

  • From germline predisposition to cancer: (i) germline pathogenic variant (MLH1/MSH2/MSH6/PMS2; EPCAM deletion), (ii) somatic “second hit” (mutation/LOH/epigenetic inactivation), (iii) dMMR and MSI leading to hypermutation and frameshifted coding sequences, (iv) clonal expansion of MSI adenomas/carcinomas with an immunogenic TME. URL: https://doi.org/10.3390/cancers16050849; https://doi.org/10.32604/or.2025.063951 (buono2024lynchsyndromefrom pages 3-5, gomezmolina2025lynchsyndromeand pages 1-2, gomezmolina2025lynchsyndromeand pages 2-3)
  • Accelerated adenoma–carcinoma sequence relative to sporadic CRC has been reported in LS, consistent with interval cancers and detection of dMMR crypts. URL: https://doi.org/10.3390/cancers16050849 (buono2024lynchsyndromefrom pages 3-5)

6) Phenotypic manifestations (clinical)

  • Cancer spectrum and penetrance: Elevated lifetime risks of colorectal cancer (CRC), endometrial cancer (EC), and several extracolonic cancers. Gene-specific risks are higher for MLH1/MSH2 and generally lower for MSH6/PMS2, though substantial and variable by cohort and surveillance intensity. URLs: https://doi.org/10.3390/cancers16050849; https://doi.org/10.32604/or.2025.063951 (buono2024lynchsyndromefrom pages 3-5, gomezmolina2025lynchsyndromeand pages 2-3)
  • Tumor biology: dMMR/MSI-H tumors are typically right-sided in CRC, hypermutated, with lymphoid infiltration and favorable immunotherapy responsiveness. URL: https://doi.org/10.3390/ijms26094394; https://doi.org/10.3390/cancers16050849 (awosika2025deficientmismatchrepair pages 3-4, buono2024lynchsyndromefrom pages 3-5)

Recent developments and latest research (2023–2024 priority)

  • Real-world implementation in England (2019 baseline): Only 44% of CRCs underwent tumor dMMR testing; among dMMR-positive tumors, only 51% received subsequent diagnostic testing; just 1.3% of all CRC patients had germline MMR testing, with marked geographic variation—indicating large gaps in universal screening and cascade to germline. Full implementation could identify ~700 additional LS index cases per year in England. URL (online 15 Feb 2024): https://doi.org/10.1038/s41431-024-01550-w (mcronald2024identificationofpeople pages 1-2, mcronald2024identificationofpeople pages 7-8)
  • Pan-cancer MSI biomarker underused for LS work-up: In a 2020–2023 series (n=4,553), MSI-high rate was 5.27% overall (endometrial 15.69%, gastric 8.54%, colorectal 7.40%), yet only 22.73% of MSI-high cases underwent germline testing; MLH1 promoter methylation could explain sporadic origin in 42.5% of MSI-high cases, but methylation testing was “barely ever requested”—highlighting reflex testing shortfalls. URL (Feb 2024): https://doi.org/10.1200/po.23.00332 (papadopoulou2024microsatelliteinstabilityis pages 1-2)
  • Immunotherapy outcomes in dMMR gynecologic cancers: A phase 2 single-arm trial of nivolumab in dMMR uterine/ovarian cancers (n=35) reported ORR 58.8%, 24-week PFS 64.7%, DCR 73.5%, median OS not reached at 42.1 months’ follow-up; safety acceptable (29% grade 3–4 TRAEs, no grade 5). URL (Apr 2024): https://doi.org/10.1038/s41591-024-02942-7 (friedman2024nivolumabformismatchrepairdeficient pages 1-2)
  • Contemporary reviews reinforce LS mechanisms and clinical strategies, including multigene testing, surveillance, and the promise of aspirin/resistant starch and vaccines targeting frameshift peptides. URLs: https://doi.org/10.3390/cancers16050849; https://doi.org/10.32604/or.2025.063951 (buono2024lynchsyndromefrom pages 3-5, gomezmolina2025lynchsyndromeand pages 1-2)

Current applications and real-world implementations

  • Universal tumor screening: IHC for MLH1/MSH2/MSH6/PMS2 and/or MSI testing; reflex MLH1 promoter methylation and BRAF V600E to triage sporadic MLH1-deficient tumors; positive cases proceed to genetic counseling and germline testing. Practical assay performance (IHC sensitivity/specificity) and pipeline considerations are summarized in recent 2024 overviews, but substantial implementation gaps persist (see above). URLs: overview (2024) [Sowter], https://doi.org/10.1038/s41431-024-01550-w; https://doi.org/10.1200/po.23.00332 (sowter2024identifyingcandidatesfor pages 45-48, mcronald2024identificationofpeople pages 1-2, papadopoulou2024microsatelliteinstabilityis pages 1-2)
  • Immunotherapy: PD-1 inhibitors (e.g., nivolumab, pembrolizumab) are effective across dMMR/MSI-H tumors; in dMMR gynecologic cancers, nivolumab achieved ORR ~59% with durable control in a phase 2 trial. URL: https://doi.org/10.1038/s41591-024-02942-7 (friedman2024nivolumabformismatchrepairdeficient pages 1-2)
  • Prevention: Aspirin chemoprevention is supported by randomized trial data historically (CAPP), with ongoing optimization of dose/implementation; resistant starch and frameshift peptide vaccines are emerging strategies discussed in 2024 reviews. URL: https://doi.org/10.3390/cancers16050849 (buono2024lynchsyndromefrom pages 3-5)

Expert opinions and authoritative guidance (2023–2024)

  • Guidance trend: Expert reviews emphasize multigene panel testing for suspected LS, universal tumor screening in incident CRC and EC, and reflex MLH1 methylation/BRAF testing before germline referral, noting continued underdiagnosis due to real-world pathway attrition. URL: https://doi.org/10.3390/cancers16050849; https://doi.org/10.1038/s41431-024-01550-w; https://doi.org/10.1200/po.23.00332 (buono2024lynchsyndromefrom pages 3-5, mcronald2024identificationofpeople pages 1-2, papadopoulou2024microsatelliteinstabilityis pages 1-2)
  • Immunotherapy perspective: High dMMR/MSI-H immunogenicity rationalizes PD-1 blockade as standard; new gynecologic-cancer data (nivolumab) add disease-specific validation and suggest microenvironmental biomarkers associated with durability (e.g., dysfunctional CD8+PD-1+ T cells). URL: https://doi.org/10.1038/s41591-024-02942-7 (friedman2024nivolumabformismatchrepairdeficient pages 1-2)

Relevant statistics and data (recent)

  • England 2019 national dataset: 44% of CRCs tested for dMMR; among dMMR, only 51% had further diagnostic testing; 1.3% of all CRC patients had germline MMR testing; estimated +700 LS cases/year with full implementation. URL: https://doi.org/10.1038/s41431-024-01550-w (mcronald2024identificationofpeople pages 1-2, mcronald2024identificationofpeople pages 7-8)
  • Real-world MSI-to-germline cascade: Only 22.73% of MSI-high cases had germline testing; MLH1 methylation could explain 42.5% sporadic origin in CRC/EC, but methylation testing rarely requested. URL: https://doi.org/10.1200/po.23.00332 (papadopoulou2024microsatelliteinstabilityis pages 1-2)
  • dMMR gynecologic cancer trial: Nivolumab ORR 58.8%, PFS24 64.7%, DCR 73.5%, median OS not reached at ~42 months’ follow-up; 29% grade 3–4 TRAEs, no grade 5. URL: https://doi.org/10.1038/s41591-024-02942-7 (friedman2024nivolumabformismatchrepairdeficient pages 1-2)

Knowledge base annotations

  • Pathophysiology description: Germline pathogenic variants in MLH1/MSH2/MSH6/PMS2 (or EPCAM deletions) predispose to cancer. Biallelic inactivation in tumors causes dMMR and MSI, leading to hypermutation and frameshift neoantigens, an inflamed tumor microenvironment, and sensitivity to PD-1 blockade. URL: https://doi.org/10.3390/cancers16050849; https://doi.org/10.3390/ijms26094394 (buono2024lynchsyndromefrom pages 3-5, awosika2025deficientmismatchrepair pages 3-4)
  • Gene/protein annotations (HGNC): MLH1; MSH2; MSH6; PMS2; EPCAM. EPCAM 3’ deletions silence MSH2 via promoter methylation. URL: https://doi.org/10.32604/or.2025.063951 (gomezmolina2025lynchsyndromeand pages 1-2)
  • GO biological processes: DNA repair (GO:0006281); response to DNA damage (GO:0006974); immune response (GO:0006955); type I interferon signaling (GO:0060337). URL: https://doi.org/10.3390/ijms26094394 (awosika2025deficientmismatchrepair pages 3-4)
  • Cellular components: Nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829). URL: https://doi.org/10.3390/ijms26094394 (awosika2025deficientmismatchrepair pages 3-4)
  • Phenotype associations (HPO): Colorectal carcinoma; endometrial carcinoma; multiple primary tumors; early-onset malignancy. URLs: https://doi.org/10.3390/cancers16050849; https://doi.org/10.32604/or.2025.063951 (buono2024lynchsyndromefrom pages 3-5, gomezmolina2025lynchsyndromeand pages 2-3)
  • Cell type involvement (CL): Colonic epithelial cells; endometrial epithelial cells; tumor-infiltrating CD8+ T cells. URL: https://doi.org/10.3390/ijms26094394 (awosika2025deficientmismatchrepair pages 3-4)
  • Anatomical locations (UBERON): Colon (UBERON:0001155), endometrium, ovary, stomach, urinary tract. URL: https://doi.org/10.3390/cancers16050849 (buono2024lynchsyndromefrom pages 3-5)
  • Chemical entities (CHEBI): Acetylsalicylic acid (CHEBI:15365) as chemoprevention under study. URL: https://doi.org/10.3390/cancers16050849 (buono2024lynchsyndromefrom pages 3-5)

Evidence items (with PMIDs or URLs)

  • Buono AD et al., 2024 (Cancers): Multidisciplinary management, molecular carcinogenesis, and prevention strategies in LS; includes aspirin/resistant starch/vaccine discussion. URL: https://doi.org/10.3390/cancers16050849 (buono2024lynchsyndromefrom pages 3-5)
  • Gómez-Molina R et al., 2025 (Oncology Research): Molecular genetics of LS, EPCAM mechanism, surveillance strategies; penetrance variation. URL: https://doi.org/10.32604/or.2025.063951 (gomezmolina2025lynchsyndromeand pages 1-2, gomezmolina2025lynchsyndromeand pages 2-3)
  • Awosika JA et al., 2025 (IJMS): Overview of dMMR/MSI across solid tumors; immunogenic profile and ICI responsiveness. URL: https://doi.org/10.3390/ijms26094394 (awosika2025deficientmismatchrepair pages 3-4)
  • McRonald F et al., 2024 (Eur J Hum Genet): England 2019 real-world LS diagnostic pathway; under-testing and under-referral; potential +700 LS/year with full implementation. URL: https://doi.org/10.1038/s41431-024-01550-w (mcronald2024identificationofpeople pages 1-2, mcronald2024identificationofpeople pages 7-8)
  • Papadopoulou E et al., 2024 (JCO Precision Oncology): MSI as biomarker; low rates of germline testing and MLH1 methylation reflex in practice. URL: https://doi.org/10.1200/po.23.00332 (papadopoulou2024microsatelliteinstabilityis pages 1-2)
  • Friedman CF et al., 2024 (Nature Medicine): Nivolumab in dMMR gynecologic cancers—ORR 58.8%, PFS24 64.7%, durable control. URL: https://doi.org/10.1038/s41591-024-02942-7 (friedman2024nivolumabformismatchrepairdeficient pages 1-2)
  • Sowter P., 2024: Screening pipelines and assay performance; IHC sensitivity/specificity context and UK testing frameworks. (sowter2024identifyingcandidatesfor pages 45-48)

Plan status and completion

Objectives were defined, evidence gathered, structured artifacts created, and the comprehensive report compiled with 2023–2024 prioritized sources and precise URLs. All objectives are completed.

References

  1. (sowter2024identifyingcandidatesfor pages 45-48): P Sowter. Identifying candidates for chemopreventative aspirin prophylaxis: improving the detection of mmrd. Unknown journal, 2024.

  2. (buono2024lynchsyndromefrom pages 3-5): Arianna Dal Buono, Alberto Puccini, Gianluca Franchellucci, Marco Airoldi, Michela Bartolini, Paolo Bianchi, Armando Santoro, Alessandro Repici, and Cesare Hassan. Lynch syndrome: from multidisciplinary management to precision prevention. Cancers, 16:849, Feb 2024. URL: https://doi.org/10.3390/cancers16050849, doi:10.3390/cancers16050849. This article has 20 citations and is from a poor quality or predatory journal.

  3. (gomezmolina2025lynchsyndromeand pages 2-3): Raquel Gómez-Molina, Raquel Martínez, Miguel Suárez, Ana PEÑA-CABIA, MARíA CONCEPCIóN Calderón, and Jorge Mateo. Lynch syndrome and colorectal cancer: a review of current perspectives in molecular genetics and clinical strategies. Oncology Research, 33:1531-1545, Jun 2025. URL: https://doi.org/10.32604/or.2025.063951, doi:10.32604/or.2025.063951. This article has 5 citations and is from a peer-reviewed journal.

  4. (pallatt2025abriefreview pages 3-5): Sneha Pallatt, Sibin Nambidi, Subhamay Adhikary, Antara Banerjee, Surajit Pathak, and Asim K. Duttaroy. A brief review of lynch syndrome: understanding the dual cancer risk between endometrial and colorectal cancer. Oncology Reviews, May 2025. URL: https://doi.org/10.3389/or.2025.1549416, doi:10.3389/or.2025.1549416. This article has 4 citations.

  5. (awosika2025deficientmismatchrepair pages 3-4): Joy A. Awosika, James L. Gulley, and Danielle M. Pastor. Deficient mismatch repair and microsatellite instability in solid tumors. International Journal of Molecular Sciences, 26:4394, May 2025. URL: https://doi.org/10.3390/ijms26094394, doi:10.3390/ijms26094394. This article has 6 citations and is from a poor quality or predatory journal.

  6. (buono2024lynchsyndromefrom pages 1-2): Arianna Dal Buono, Alberto Puccini, Gianluca Franchellucci, Marco Airoldi, Michela Bartolini, Paolo Bianchi, Armando Santoro, Alessandro Repici, and Cesare Hassan. Lynch syndrome: from multidisciplinary management to precision prevention. Cancers, 16:849, Feb 2024. URL: https://doi.org/10.3390/cancers16050849, doi:10.3390/cancers16050849. This article has 20 citations and is from a poor quality or predatory journal.

  7. (mcronald2024identificationofpeople pages 1-2): Fiona E. McRonald, Joanna Pethick, Francesco Santaniello, Brian Shand, Adele Tyson, Oliver Tulloch, Shilpi Goel, Margreet Lüchtenborg, Gillian M. Borthwick, Clare Turnbull, Adam C. Shaw, Kevin J. Monahan, Ian M. Frayling, Steven Hardy, and John Burn. Identification of people with lynch syndrome from those presenting with colorectal cancer in england: baseline analysis of the diagnostic pathway. European Journal of Human Genetics, 32:529-538, Feb 2024. URL: https://doi.org/10.1038/s41431-024-01550-w, doi:10.1038/s41431-024-01550-w. This article has 13 citations and is from a domain leading peer-reviewed journal.

  8. (papadopoulou2024microsatelliteinstabilityis pages 1-2): Eirini Papadopoulou, George Rigas, Elena Fountzilas, Anastasios Boutis, Stylianos Giassas, Nikolaos Mitsimponas, Danai Daliani, Dimitrios C Ziogas, Michalis Liontos, Vasileios Ramfidis, Charalampos Christophilakis, Dimitris Matthaios, Theofanis Floros, Chrysiida Florou-Chatzigiannidou, Konstantinos Agiannitopoulos, Angeliki Meintani, Aikaterini Tsantikidi, Anastasia Katseli, Kevisa Potska, Georgios Tsaousis, Vasiliki Metaxa-Mariatou, and George Nasioulas. Microsatellite instability is insufficiently used as a biomarker for lynch syndrome testing in clinical practice. JCO Precision Oncology, Feb 2024. URL: https://doi.org/10.1200/po.23.00332, doi:10.1200/po.23.00332. This article has 13 citations and is from a peer-reviewed journal.

  9. (friedman2024nivolumabformismatchrepairdeficient pages 1-2): Claire F. Friedman, Beryl L. Manning-Geist, Qin Zhou, Tara Soumerai, Aliya Holland, Arnaud Da Cruz Paula, Hunter Green, Melih Arda Ozsoy, Alexia Iasonos, Travis Hollmann, Mario M. Leitao, Jennifer J. Mueller, Vicky Makker, William P. Tew, Roisin E. O’Cearbhaill, Ying L. Liu, Maria M. Rubinstein, Tiffany Troso-Sandoval, Stuart M. Lichtman, Alison Schram, Chrisann Kyi, Rachel N. Grisham, Pamela Causa Andrieu, E. John Wherry, Carol Aghajanian, Britta Weigelt, Martee L. Hensley, and Dmitriy Zamarin. Nivolumab for mismatch-repair-deficient or hypermutated gynecologic cancers: a phase 2 trial with biomarker analyses. Nature Medicine, 30:1330-1338, Apr 2024. URL: https://doi.org/10.1038/s41591-024-02942-7, doi:10.1038/s41591-024-02942-7. This article has 22 citations and is from a highest quality peer-reviewed journal.

  10. (ranganathan2023prevalenceandclinical pages 10-11): Megha Ranganathan, Rosalba E. Sacca, Magan Trottier, Anna Maio, Yelena Kemel, Erin Salo-Mullen, Amanda Catchings, Sarah Kane, Chiyun Wang, Vignesh Ravichandran, Ryan Ptashkin, Nikita Mehta, Julio Garcia-Aguilar, Martin R. Weiser, Mark T.A. Donoghue, Michael F. Berger, Diana Mandelker, Michael F. Walsh, Maria Carlo, Ying L. Liu, Andrea Cercek, Rona Yaeger, Leonard Saltz, Neil H. Segal, Robin B. Mendelsohn, Arnold J. Markowitz, Kenneth Offit, Jinru Shia, Zsofia K. Stadler, and Alicia Latham. Prevalence and clinical implications of mismatch repair-proficient colorectal cancer in patients with lynch syndrome. JCO Precision Oncology, May 2023. URL: https://doi.org/10.1200/po.22.00675, doi:10.1200/po.22.00675. This article has 15 citations and is from a peer-reviewed journal.

  11. (gomezmolina2025lynchsyndromeand pages 1-2): Raquel Gómez-Molina, Raquel Martínez, Miguel Suárez, Ana PEÑA-CABIA, MARíA CONCEPCIóN Calderón, and Jorge Mateo. Lynch syndrome and colorectal cancer: a review of current perspectives in molecular genetics and clinical strategies. Oncology Research, 33:1531-1545, Jun 2025. URL: https://doi.org/10.32604/or.2025.063951, doi:10.32604/or.2025.063951. This article has 5 citations and is from a peer-reviewed journal.

  12. (mcronald2024identificationofpeople pages 7-8): Fiona E. McRonald, Joanna Pethick, Francesco Santaniello, Brian Shand, Adele Tyson, Oliver Tulloch, Shilpi Goel, Margreet Lüchtenborg, Gillian M. Borthwick, Clare Turnbull, Adam C. Shaw, Kevin J. Monahan, Ian M. Frayling, Steven Hardy, and John Burn. Identification of people with lynch syndrome from those presenting with colorectal cancer in england: baseline analysis of the diagnostic pathway. European Journal of Human Genetics, 32:529-538, Feb 2024. URL: https://doi.org/10.1038/s41431-024-01550-w, doi:10.1038/s41431-024-01550-w. This article has 13 citations and is from a domain leading peer-reviewed journal.

{ }

Source YAML

click to show 
name: Lynch Syndrome
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-02-17T21:53:14Z'
description: Lynch syndrome is an autosomal dominant hereditary cancer
  predisposition syndrome caused by germline mutations in DNA mismatch repair
  genes (MLH1, MSH2, MSH6, PMS2). It significantly increases the risk of
  colorectal, endometrial, ovarian, and other cancers, typically presenting at
  younger ages than sporadic cancers.
categories:
- Hereditary Cancer Syndrome
- Colorectal Cancer Predisposition
has_subtypes:
- name: MLH1 Mutation
  description: Caused by a mutation in the MLH1 gene, which is involved in DNA
    mismatch repair.
  evidence:
  - reference: PMID:19466295
    reference_title: "Mismatch repair genes in Lynch syndrome: a review."
    supports: SUPPORT
    snippet: Lynch syndrome represents 1-7% of all cases of colorectal cancer
      and is an autosomal-dominant inherited cancer predisposition syndrome
      caused by germline mutations in deoxyribonucleic acid (DNA) mismatch
      repair genes
    explanation: The literature confirms that Lynch Syndrome is caused by
      germline mutations in DNA mismatch repair genes, including MLH1.
  - reference: PMID:38003003
    reference_title: "MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis."
    supports: SUPPORT
    snippet: MLH1 hypermethylation is an epigenetic alteration in the
      tumorigenesis of colorectal cancer (CRC) and endometrial cancer (EC),
      causing gene silencing, and, as a consequence, microsatellite instability.
    explanation: The literature discusses MLH1 gene involvement in Lynch
      Syndrome, supporting its significant role.
  - reference: PMID:34091457
    reference_title: "MLH1 Exon 12 Gene Deletion Leading to Lynch Syndrome: A Case Report."
    supports: SUPPORT
    snippet: Deleterious heterozygous mutation of the MLH1 gene is an important
      cause of Lynch syndrome (LS), an autosomal dominant cancer caused by
      functional defects in the DNA mismatch repair (MMR) complex.
    explanation: The abstract confirms that mutations in the MLH1 gene are a
      significant cause of Lynch Syndrome.
- name: MSH2 Mutation
  description: Caused by a mutation in the MSH2 gene, which is involved in DNA
    mismatch repair.
  evidence:
  - reference: PMID:19466295
    reference_title: "Mismatch repair genes in Lynch syndrome: a review."
    supports: SUPPORT
    snippet: 'Lynch syndrome represents 1-7% of all cases of colorectal cancer and
      is an autosomal-dominant inherited cancer predisposition syndrome caused by
      germline mutations in deoxyribonucleic acid (DNA) mismatch repair genes. Since
      the discovery of the major human genes with DNA mismatch repair function, mutations
      in five of them have been correlated with susceptibility to Lynch syndrome:
      mutS homolog 2 (MSH2); mutL homolog 1 (MLH1); mutS homolog 6 (MSH6); postmeiotic
      segregation increased 2 (PMS2); and postmeiotic segregation increased 1 (PMS1).'
    explanation: The literature indicates that MSH2 is one of the genes whose
      mutation is correlated with susceptibility to Lynch syndrome.
  - reference: PMID:34302852
    reference_title: "The coding microsatellite mutation profile of PMS2-deficient colorectal cancer."
    supports: SUPPORT
    snippet: 'Lynch syndrome (LS) is caused by a pathogenic heterozygous germline
      variant in one of the DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2.'
    explanation: This directly supports the statement that Lynch syndrome
      subtypes include those caused by mutations in the MSH2 gene.
  - reference: PMID:36434153
    reference_title: "Lynch syndrome, molecular mechanisms and variant classification."
    supports: SUPPORT
    snippet: Patients with the heritable cancer disease, Lynch syndrome, carry
      germline variants in the MLH1, MSH2, MSH6 and PMS2 genes, encoding the
      central components of the DNA mismatch repair system.
    explanation: This provides further confirmation that mutations in MSH2 can
      cause Lynch syndrome, supporting the statement.
- name: MSH6 Mutation
  description: Caused by a mutation in the MSH6 gene, which is involved in DNA
    mismatch repair.
  evidence:
  - reference: PMID:19466295
    reference_title: "Mismatch repair genes in Lynch syndrome: a review."
    supports: SUPPORT
    snippet: 'Since the discovery of the major human genes with DNA mismatch repair
      function, mutations in five of them have been correlated with susceptibility
      to Lynch syndrome: mutS homolog 2 (MSH2); mutL homolog 1 (MLH1); mutS homolog
      6 (MSH6); postmeiotic segregation increased 2 (PMS2); and postmeiotic segregation
      increased 1 (PMS1).'
    explanation: The literature confirms that Lynch syndrome can be caused by
      mutations in the MSH6 gene, which is involved in DNA mismatch repair.
  - reference: PMID:25430799
    reference_title: "Genetic features of Lynch syndrome in the Israeli population."
    supports: SUPPORT
    snippet: Sixty-seven (59%) families had mutations in MSH2, 20 (18%) in MSH6,
      19 (17%) in MLH1 and 7 (6%) in PMS2.
    explanation: The study identifies MSH6 as one of the genes with mutations
      found in Lynch syndrome patients.
- name: PMS2 Mutation
  description: Caused by a mutation in the PMS2 gene, which is involved in DNA
    mismatch repair.
  evidence:
  - reference: PMID:24027009
    reference_title: "Inactivation of DNA mismatch repair by variants of uncertain significance in the PMS2 gene."
    supports: SUPPORT
    snippet: Lynch syndrome (LS) is a common cancer predisposition caused by an
      inactivating mutation in one of four DNA mismatch repair (MMR) genes.
    explanation: Further detail is provided in the study focusing on PMS2 gene's
      role in MMR and its link to Lynch Syndrome.
  - reference: PMID:18602922
    reference_title: "The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations."
    supports: SUPPORT
    snippet: Although the clinical phenotype of Lynch syndrome (also known as
      hereditary nonpolyposis colorectal cancer) has been well described, little
      is known about disease in PMS2 mutation carriers.
    explanation: The study confirms PMS2 mutations contribute to Lynch Syndrome.
- name: EPCAM Deletion
  description: Caused by a deletion in the EPCAM gene, which can lead to
    silencing of the MSH2 gene.
  evidence:
  - reference: PMID:23411950
    reference_title: "[A novel genetic disorder of Lynch syndrome - EPCAM gene deletion]."
    supports: SUPPORT
    snippet: Germline mutations of 4 MMR genes, e.g., MLH1, MSH2, MSH6 and PMS2,
      had been identified as the cause of this disease, however, a novel
      mechanism, epigenetic inactivation of MSH2 gene due to hypermethylation of
      promotor region by the deletion of 3'part of epithelial cell adhesion
      molecule(EPCAM) gene which is located upstream of the MSH2 gene, has been
      reported in recent years.
    explanation: This reference describes the mechanism by which EPCAM gene
      deletion causes epigenetic inactivation of the MSH2 gene, supporting the
      statement.
  - reference: PMID:30461124
    reference_title: "EPCAM mutation update: Variants associated with congenital tufting enteropathy and Lynch syndrome."
    supports: SUPPORT
    snippet: Monoallelic deletions of the 3' end of EPCAM that silence the
      downstream gene, MSH2, cause a form of Lynch syndrome, which is a cancer
      predisposition syndrome associated with loss of DNA mismatch repair.
    explanation: This reference further supports the statement by specifying
      that deletions of the EPCAM gene silence the MSH2 gene, leading to Lynch
      syndrome.
  - reference: PMID:23264089
    reference_title: "EPCAM deletion carriers constitute a unique subgroup of Lynch syndrome patients."
    supports: SUPPORT
    snippet: These patients carry deletions of the 3' end of the EPCAM gene,
      including its polyadenylation signal. Due to concomitant transcriptional
      read-through of EPCAM, the promoter of MSH2 15 kb further downstream
      becomes inactivated through hypermethylation.
    explanation: This reference describes the specific mechanism by which EPCAM
      deletions lead to the inactivation of MSH2, supporting the statement.
prevalence:
- population: General Population (MMR pathogenic variant carriers)
  percentage: 0.3-0.4
  evidence:
  - reference: PMID:33357406
    reference_title: "Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk."
    supports: SUPPORT
    snippet: Due to high prevalence in the general population (≥1:300),6,7 clear
      genetic etiology, and potential for prevention through intensified
      surveillance, pathogenic MMR gene variants are considered clinically
      actionable.
    explanation: This directly supports a high general-population carrier
      prevalence on the order of approximately 0.3%.
  - reference: PMID:34630437
    reference_title: "Lynch Syndrome and MSI-H Cancers: From Mechanisms to \"Off-The-Shelf\" Cancer Vaccines."
    supports: SUPPORT
    snippet: These Lynch syndrome pathogenic alleles are widely present in
      humans at a 1:320 population frequency of a single allele
    explanation: A population frequency of approximately 1:320 corresponds to
      about 0.3%, consistent with the stated range.
pathophysiology:
- name: DNA Mismatch Repair Deficiency
  description: Mutations in mismatch repair genes lead to an accumulation of DNA
    replication errors.
  locations:
  - preferred_term: nucleus
    term:
      id: GO:0005634
      label: nucleus
  cell_types:
  - preferred_term: colonic epithelial cell
    term:
      id: CL:0011108
      label: colon epithelial cell
  - preferred_term: endometrial epithelial cell
    term:
      id: CL:0002656
      label: glandular endometrial unciliated epithelial cell
  cellular_components:
  - preferred_term: nucleoplasm
    term:
      id: GO:0005654
      label: nucleoplasm
  protein_complexes:
  - preferred_term: mismatch repair complex
    term:
      id: GO:0032300
      label: mismatch repair complex
  biological_processes:
  - preferred_term: mismatch repair
    modifier: DECREASED
    term:
      id: GO:0006298
      label: mismatch repair
  - preferred_term: DNA-templated DNA replication maintenance of fidelity
    modifier: DECREASED
    term:
      id: GO:0045005
      label: DNA-templated DNA replication maintenance of fidelity
  - preferred_term: DNA damage response
    modifier: ABNORMAL
    term:
      id: GO:0006974
      label: DNA damage response
  downstream:
  - target: Microsatellite Instability
    description: Loss of mismatch repair causes unstable microsatellite repeats
      and increased insertion-deletion burden.
    evidence:
    - reference: PMID:25701956
      reference_title: "Microsatellite instability: an update."
      supports: SUPPORT
      snippet: Deficient DNA mismatch repair (MMR) results in a strong mutator
        phenotype known as microsatellite instability (MSI), which is a hallmark
        of Lynch syndrome-associated cancers.
      explanation: This directly supports the mechanistic edge from mismatch
        repair deficiency to microsatellite instability.
  evidence:
  - reference: PMID:19466295
    reference_title: "Mismatch repair genes in Lynch syndrome: a review."
    supports: SUPPORT
    snippet: Lynch syndrome represents 1-7% of all cases of colorectal cancer
      and is an autosomal-dominant inherited cancer predisposition syndrome
      caused by germline mutations in deoxyribonucleic acid (DNA) mismatch
      repair genes.
    explanation: This reference confirms that Lynch Syndrome involves mutations
      in mismatch repair genes.
  - reference: PMID:29233924
    reference_title: "DNA mismatch repair preferentially protects genes from mutation."
    supports: SUPPORT
    snippet: Many mutations first arise as DNA replication errors. These errors
      subsequently evade correction by cellular DNA repair, for example, by the
      well-known DNA mismatch repair (MMR) mechanism.
    explanation: This supports the notion that DNA mismatch repair is crucial in
      correcting DNA replication errors, and its deficiency leads to the
      accumulation of these errors.
  - reference: PMID:34919656
    reference_title: "Induction of mismatch repair deficiency, compromised DNA damage signaling and compound hypermutagenesis by a dietary mutagen in a cell-based model for Lynch syndrome."
    supports: SUPPORT
    snippet: 'Lynch syndrome (LS, OMIM #120435) is caused by an inherited heterozygous
      defect in any of the four core DNA mismatch repair (MMR) genes MSH2, MSH6, MLH1
      or PMS2...'
    explanation: Clear evidence linking inherited defects in mismatch repair
      genes to Lynch Syndrome.
  - reference: PMID:24443998
    reference_title: "Epigenetic mechanisms in the pathogenesis of Lynch syndrome."
    supports: SUPPORT
    snippet: Inherited defects in the DNA mismatch repair (MMR) system, MLH1,
      MSH2, MSH6, and PMS2 genes, underlie Lynch syndrome, one of the most
      prevalent cancer syndromes in man.
    explanation: Validates that Lynch Syndrome is underpinned by mutations in
      specific mismatch repair genes.
- name: Microsatellite Instability
  description: Defective mismatch repair causes variations in the length of
    repetitive DNA sequences called microsatellites.
  locations:
  - preferred_term: colon
    term:
      id: UBERON:0001155
      label: colon
  - preferred_term: endometrium
    term:
      id: UBERON:0001295
      label: endometrium
  cell_types:
  - preferred_term: colonic epithelial cell
    term:
      id: CL:0011108
      label: colon epithelial cell
  - preferred_term: endometrial epithelial cell
    term:
      id: CL:0002656
      label: glandular endometrial unciliated epithelial cell
  biological_processes:
  - preferred_term: DNA-templated DNA replication maintenance of fidelity
    modifier: DECREASED
    term:
      id: GO:0045005
      label: DNA-templated DNA replication maintenance of fidelity
  downstream:
  - target: Accelerated Tumor Development
    description: MSI-associated coding frameshift mutations increase oncogenic
      transformation risk.
    evidence:
    - reference: PMID:38466935
      reference_title: "Frameshift mutations in peripheral blood as a biomarker for surveillance of Lynch syndrome."
      supports: SUPPORT
      snippet: Lynch syndrome is a hereditary cancer predisposition syndrome
        caused by germline mutations in DNA mismatch repair genes, which lead to
        high microsatellite instability and frameshift mutations at coding
        mononucleotide repeats in the genome.
      explanation: This supports MSI-associated frameshift mutagenesis as a
        driver of rapid tumorigenesis.
  - target: Neoantigen Generation and Immune Activation
    description: Frameshifted proteins generate immunogenic neoepitopes.
    evidence:
    - reference: PMID:34630437
      reference_title: "Lynch Syndrome and MSI-H Cancers: From Mechanisms to \"Off-The-Shelf\" Cancer Vaccines."
      supports: SUPPORT
      snippet: We and others have characterized a subset of MSI-H associated
        highly recurrent frameshift mutations that yield shared immunogenic
        neoantigens.
      explanation: This directly supports the causal edge from MSI-associated
        frameshift mutations to neoantigen generation.
  evidence:
  - reference: PMID:25701956
    reference_title: "Microsatellite instability: an update."
    supports: SUPPORT
    snippet: Deficient DNA mismatch repair (MMR) results in a strong mutator
      phenotype known as microsatellite instability (MSI), which is a hallmark
      of Lynch syndrome-associated cancers.
    explanation: The snippet confirms that defective mismatch repair causes
      microsatellite instability, supporting the statement.
  - reference: PMID:35315099
    reference_title: "Review article: Lynch Syndrome-a mechanistic and clinical management update."
    supports: SUPPORT
    snippet: LS tumours are characterised by unique pathogenesis, ultimately
      resulting in hypermutation, microsatellite instability and high
      immunogenicity that has significant implications for cancer risk, clinical
      presentation, treatment and surveillance.
    explanation: The statement is supported by the evidence that Lynch Syndrome
      leads to microsatellite instability due to defective mismatch repair.
  - reference: PMID:31273487
    reference_title: "Genetic and genomic basis of the mismatch repair system involved in Lynch syndrome."
    supports: SUPPORT
    snippet: Lynch syndrome is a state of mismatch repair deficiency due to a
      monoallelic abnormality of any mismatch repair genes. The phenotype
      indicating the mismatch repair deficiency can be frequently shown as a
      microsatellite instability in tumors.
    explanation: This reference supports the statement by linking mismatch
      repair deficiency and microsatellite instability in Lynch Syndrome.
  - reference: PMID:38466935
    reference_title: "Frameshift mutations in peripheral blood as a biomarker for surveillance of Lynch syndrome."
    supports: SUPPORT
    snippet: Lynch syndrome is a hereditary cancer predisposition syndrome
      caused by germline mutations in DNA mismatch repair genes, which lead to
      high microsatellite instability and frameshift mutations at coding
      mononucleotide repeats in the genome.
    explanation: The snippet supports the statement by describing how defective
      mismatch repair in Lynch syndrome leads to microsatellite instability.
- name: Accelerated Tumor Development
  description: The accumulation of mutations in key genes leads to an increased
    risk of developing certain cancers at an earlier age.
  locations:
  - preferred_term: colon
    term:
      id: UBERON:0001155
      label: colon
  - preferred_term: endometrium
    term:
      id: UBERON:0001295
      label: endometrium
  cell_types:
  - preferred_term: colonic epithelial cell
    term:
      id: CL:0011108
      label: colon epithelial cell
  - preferred_term: endometrial epithelial cell
    term:
      id: CL:0002656
      label: glandular endometrial unciliated epithelial cell
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:37478804
    reference_title: "Advances in vaccine development for cancer prevention and treatment in Lynch Syndrome."
    supports: SUPPORT
    snippet: Lynch Syndrome (LS) is one of the most common hereditary cancer
      syndromes, and is caused by mutations in one of the four DNA mismatch
      repair (MMR) genes, namely MLH1, MSH2, MSH6 and PMS2.
    explanation: This further supports the fact that accumulation of mutations
      in key genes (MMR genes) in Lynch Syndrome contributes to an increased
      risk of developing certain cancers.
  - reference: PMID:23604856
    reference_title: "Cancer risk in Lynch Syndrome."
    supports: SUPPORT
    snippet: Lynch Syndrome, or hereditary non-polyposis colorectal cancer
      (HNPCC) is an autosomal dominant cancer predisposition syndrome caused by
      inactivating mutations in DNA mismatch repair genes.
    explanation: This supports the idea that the mechanism of Lynch Syndrome
      involves the accumulation of mutations in key genes leading to cancer.
- name: Neoantigen Generation and Immune Activation
  description: Frameshift mutations in coding repeats generate tumor neoantigens
    that activate tumor-infiltrating lymphocytes and create an immunogenic tumor
    microenvironment.
  locations:
  - preferred_term: colon
    term:
      id: UBERON:0001155
      label: colon
  - preferred_term: endometrium
    term:
      id: UBERON:0001295
      label: endometrium
  cell_types:
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: antigen processing and presentation of peptide antigen via
      MHC class I
    modifier: INCREASED
    term:
      id: GO:0002474
      label: antigen processing and presentation of peptide antigen via MHC
        class I
  - preferred_term: type I interferon-mediated signaling pathway
    modifier: INCREASED
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
  - preferred_term: T cell mediated cytotoxicity directed against tumor cell
      target
    modifier: INCREASED
    term:
      id: GO:0002419
      label: T cell mediated cytotoxicity directed against tumor cell target
  downstream:
  - target: Immune Checkpoint Blockade Sensitivity
    description: High neoantigen load and cytotoxic T-cell infiltration create
      therapeutic vulnerability to PD-1 blockade.
    evidence:
    - reference: PMID:37625240
      reference_title: "Efficacy of PD-1 inhibitors for colorectal cancer and polyps in Lynch syndrome patients."
      supports: SUPPORT
      snippet: PD-1 inhibitors are highly effective for dMMR and MSI-H LS CRCs,
        but not for pMMR or MSS LS CRCs or mucinous/signet-ring cell CRC.
      explanation: This supports the causal link between immunogenic dMMR/MSI
        biology and checkpoint blockade sensitivity.
  evidence:
  - reference: PMID:34630437
    reference_title: "Lynch Syndrome and MSI-H Cancers: From Mechanisms to \"Off-The-Shelf\" Cancer Vaccines."
    supports: SUPPORT
    snippet: We and others have characterized a subset of MSI-H associated
      highly recurrent frameshift mutations that yield shared immunogenic
      neoantigens.
    explanation: This directly supports neoantigen generation from recurrent
      frameshift events in mismatch repair-deficient, MSI-high tumors seen in
      Lynch syndrome.
  - reference: PMID:35315099
    reference_title: "Review article: Lynch Syndrome-a mechanistic and clinical management update."
    supports: SUPPORT
    snippet: LS tumours are characterised by unique pathogenesis, ultimately
      resulting in hypermutation, microsatellite instability and high
      immunogenicity that has significant implications for cancer risk, clinical
      presentation, treatment and surveillance.
    explanation: This supports the immunogenic tumor microenvironment and immune
      activation component of this mechanism.
  notes: The hypermutated phenotype leads to high tumor mutational burden and
    neoantigen presentation, explaining sensitivity to immune checkpoint
    inhibitors.
- name: Immune Checkpoint Blockade Sensitivity
  description: Lynch-associated dMMR/MSI tumors with high neoantigen burden are
    enriched for anti-tumor T-cell activity and show strong responses to PD-1
    blockade.
  biological_processes:
  - preferred_term: T cell mediated cytotoxicity directed against tumor cell
      target
    modifier: INCREASED
    term:
      id: GO:0002419
      label: T cell mediated cytotoxicity directed against tumor cell target
  evidence:
  - reference: PMID:37625240
    reference_title: "Efficacy of PD-1 inhibitors for colorectal cancer and polyps in Lynch syndrome patients."
    supports: SUPPORT
    snippet: PD-1 inhibitors are highly effective for dMMR and MSI-H LS CRCs,
      but not for pMMR or MSS LS CRCs or mucinous/signet-ring cell CRC.
    explanation: This human clinical observation supports mechanistic
      sensitivity of dMMR/MSI Lynch tumors to immune checkpoint blockade.
  - reference: PMID:37845474
    reference_title: "Neoplasia risk in patients with Lynch syndrome treated with immune checkpoint blockade."
    supports: PARTIAL
    snippet: Metastatic and localized mismatch repair-deficient (dMMR) tumors
      are exquisitely sensitive to immune checkpoint blockade (ICB).
    explanation: This supports high treatment sensitivity in dMMR states while
      also indicating that surveillance remains necessary.
phenotypes:
- category: Gastrointestinal
  name: Colorectal Cancer
  description: Early-onset colorectal adenocarcinoma, often right-sided with
    mucinous histology and microsatellite instability.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: colorectal cancer
    term:
      id: MONDO:0005575
      label: colorectal cancer
  sequelae:
  - target: Metastatic Disease
    description: Spread of cancer cells to distant organs including liver, lung,
      and peritoneum.
    evidence:
    - reference: PMID:37262391
      reference_title: "Prevalence and Clinical Implications of Mismatch Repair-Proficient Colorectal Cancer in Patients With Lynch Syndrome."
      supports: SUPPORT
      snippet: 60% (6 of 10) of MMR-P CRCs were metastatic compared with 13% (12
        of 89) of MMR-D CRCs.
      explanation: This study demonstrates that Lynch syndrome colorectal
        cancers can progress to metastatic disease.
  - target: Bowel Obstruction
    description: Mechanical blockage of the intestine caused by tumor growth.
    evidence:
    - reference: PMID:28722918
      reference_title: "Large Bowel Obstruction."
      supports: SUPPORT
      snippet: In some cases, an obstruction is the first clinical sign of
        colorectal carcinoma, particularly left-sided carcinoma, and up to 25%
        of colorectal carcinomas present as large bowel obstruction.
      explanation: This reference establishes that colorectal cancer causes
        bowel obstruction in up to 25% of cases.
  evidence:
  - reference: PMID:37088804
    reference_title: "Lynch syndrome: influence of additional susceptibility variants on cancer risk."
    supports: PARTIAL
    snippet: Some patients with Lynch syndrome (LS) have extreme phenotypes,
      i.e. cancer before the recommended screening age, or cancer for which
      there are no screening guidelines.
    explanation: While this study mentions patients with Lynch syndrome having
      early-onset cancer, it does not specify whether it includes colorectal
      cancer or not. It partially supports the statement on phenotypes.
  - reference: PMID:16136388
    reference_title: "Surveillance in Lynch syndrome."
    supports: SUPPORT
    snippet: The major aim of surveillance in Lynch syndrome is to diagnose
      malignant or premalignant lesions at the asymptomatic stage by regular
      checkups, particularly in the large bowel.
    explanation: Supports the high frequency of colorectal cancer diagnosis in
      Lynch syndrome as a major phenotype.
  - reference: PMID:29071502
    reference_title: "Phenotypic and genotypic heterogeneity of Lynch syndrome: a complex diagnostic challenge."
    supports: SUPPORT
    snippet: Lynch syndrome is the hereditary disorder that most frequently
      predisposes to colorectal cancer...
    explanation: Affirms that Lynch syndrome frequently predisposes to
      colorectal cancer, supporting a high-frequency diagnostic.
  - reference: PMID:23681793
    reference_title: "Value-based healthcare in Lynch syndrome."
    supports: SUPPORT
    snippet: Lynch syndrome (LS), one of the most frequent forms of hereditary
      colorectal cancer (CRC)...
    explanation: This supports the statement mentioning Lynch syndrome as
      frequently associated with hereditary colorectal cancer.
  - reference: PMID:34798988
    reference_title: "Lynch Syndrome-Associated Cancers Beyond Colorectal Cancer."
    supports: SUPPORT
    snippet: Lynch syndrome (LS) is a common form of inherited cancer
      susceptibility, which predisposes to colorectal cancer (CRC)...
    explanation: This reference supports the common occurrence of colorectal
      cancer in individuals with Lynch syndrome.
  - reference: PMID:36031446
    reference_title: "Survival outcomes associated with Lynch syndrome colorectal cancer and metachronous rate after subtotal/total versus segmental colectomy: Meta-analysis."
    supports: SUPPORT
    snippet: Lynch syndrome is associated with the most common form of heritable
      bowel cancer.
    explanation: This supports that colorectal cancer is a common
      gastrointestinal phenotype in Lynch syndrome.
  - reference: PMID:26974895
    reference_title: "A Practical Approach to the Evaluation of Gastrointestinal Tract Carcinomas for Lynch Syndrome."
    supports: SUPPORT
    snippet: Lynch syndrome accounts for roughly 1 of every 35 patients with
      colorectal carcinoma, making it the most common hereditary form of
      colorectal carcinoma.
    explanation: This directly supports the statement that colorectal cancer is
      a frequent diagnostic and phenotype in Lynch syndrome.
  - reference: PMID:21325953
    reference_title: "Lynch syndrome and MYH-associated polyposis: review and testing strategy."
    supports: SUPPORT
    snippet: Individuals with Lynch syndrome have an increased risk for
      colorectal cancer...
    explanation: Supports the high frequency of colorectal cancer in individuals
      with Lynch syndrome.
  - reference: PMID:35306248
    reference_title: "Experiences of living with Lynch Syndrome: A reflexive thematic analysis."
    supports: SUPPORT
    snippet: Lynch Syndrome carriers are at increased lifetime risk of
      developing certain cancers, such as colorectal and endometrial.
    explanation: Supports the statement of colorectal cancer phenotype in Lynch
      syndrome as it emphasizes colorectal cancer risk.
- category: Gynecologic
  name: Endometrial Cancer
  description: Uterine cancer developing at younger ages than sporadic cases,
    often the sentinel cancer in female Lynch syndrome carriers.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: endometrial cancer
    term:
      id: MONDO:0011962
      label: endometrial cancer
  evidence:
  - reference: PMID:28376523
    reference_title: "Lynch Syndrome and Endometrial Cancer."
    supports: SUPPORT
    snippet: The clinical characteristics of Lynch-associated endometrial cancer
      and screening and risk-reducing strategies also are described.
    explanation: The article discusses Lynch syndrome and its association with
      endometrial cancer, supporting the statement.
  - reference: PMID:23681793
    reference_title: "Value-based healthcare in Lynch syndrome."
    supports: SUPPORT
    snippet: Carriers of MMR defects have a strongly increased risk of
      developing CRC and endometrial cancer.
    explanation: The article states that Lynch syndrome carriers have a strongly
      increased risk of developing endometrial cancer.
  - reference: PMID:29071502
    reference_title: "Phenotypic and genotypic heterogeneity of Lynch syndrome: a complex diagnostic challenge."
    supports: SUPPORT
    snippet: Lynch syndrome is the hereditary disorder that most frequently
      predisposes to colorectal cancer as well as predisposing to a number of
      extracolonic cancers, most prominently endometrial cancer.
    explanation: The review confirms that Lynch syndrome prominently predisposes
      individuals to endometrial cancer.
  - reference: PMID:37728516
    reference_title: "Methylated DNA Markers for Sporadic Colorectal and Endometrial Cancer Are Strongly Associated with Lynch Syndrome Cancers."
    supports: SUPPORT
    snippet: Lynch syndrome (LS) markedly increases risks of colorectal and
      endometrial cancers.
    explanation: This reference further supports the statement that Lynch
      syndrome is strongly associated with endometrial cancer.
- category: Gastrointestinal
  name: Stomach Cancer
  description: Gastric adenocarcinoma occurring at elevated rates in Lynch
    syndrome, particularly with certain MMR gene mutations.
  frequency: FREQUENT
  evidence:
  - reference: PMID:31319185
    reference_title: "Clinical Factors Associated With Gastric Cancer in Individuals With Lynch Syndrome."
    supports: SUPPORT
    snippet: Lynch syndrome is the most common inherited cause of
      gastrointestinal cancer and increases risk for a variety of malignancies,
      including gastric cancer.
    explanation: The reference supports the increased frequency of stomach
      (gastric) cancer as a phenotype of Lynch Syndrome.
  - reference: PMID:27546846
    reference_title: "Heritable Gastrointestinal Cancer Syndromes."
    supports: PARTIAL
    snippet: Approximately 5% arise from germline mutations in genes associated
      with cancer predisposition.
    explanation: While this provides general context about hereditary
      gastrointestinal cancers, it does not specify Lynch Syndrome or stomach
      cancer.
  phenotype_term:
    preferred_term: Stomach Cancer
    term:
      id: HP:0012126
      label: Stomach cancer
- category: Genitourinary
  frequency: OCCASIONAL
  name: Urinary Tract Cancer
  description: Upper urinary tract urothelial carcinoma affecting the ureter or
    renal pelvis.
  phenotype_term:
    preferred_term: renal pelvis/ureter urothelial carcinoma
    term:
      id: MONDO:0020654
      label: renal pelvis/ureter urothelial carcinoma
  notes: Transitional cell carcinoma of the ureter or renal pelvis
  evidence:
  - reference: PMID:31615790
    reference_title: "Clinical Factors Associated with Urinary Tract Cancer in Individuals with Lynch Syndrome."
    supports: SUPPORT
    snippet: Lynch syndrome confers markedly increased risks of various
      malignancies, including urinary tract cancers (UTC; renal pelvis, ureter,
      bladder, and possibly kidney cancers).
    explanation: This large cohort supports urinary tract cancer as a recognized
      Lynch-associated malignancy and informs clinical risk stratification.
  - reference: PMID:21419447
    reference_title: "Upper urinary tract carcinoma in Lynch syndrome cases."
    supports: SUPPORT
    snippet: Patients with Lynch syndrome are much more likely to have generally
      rare upper urinary tract urothelial carcinoma but not bladder urothelial
      carcinoma.
    explanation: The literature supports the occurrence of upper urinary tract
      cancer (urothelial carcinoma) in patients with Lynch syndrome, which
      includes transitional cell carcinoma of the ureter or renal pelvis.
  - reference: PMID:34798988
    reference_title: "Lynch Syndrome-Associated Cancers Beyond Colorectal Cancer."
    supports: SUPPORT
    snippet: Lynch syndrome (LS) is a common form of inherited cancer
      susceptibility, which predisposes to colorectal cancer (CRC) along with a
      wide array of other extracolonic malignancies, including other
      gastrointestinal cancers, cancers of the gynecologic and genitourinary
      tracts, and other organ sites.
    explanation: The literature confirms that Lynch syndrome is associated with
      cancers of the genitourinary tract, which includes urinary tract cancer.
  - reference: PMID:23700068
    reference_title: "Surveillance for urinary tract cancer in Lynch syndrome."
    supports: SUPPORT
    snippet: Urinary tract cancers (UTC) have in many studies been reported
      increased in LS and it has been discussed among researchers and clinicians
      whether or not screening for urological tumours should be included in the
      surveillance programme.
    explanation: This review supports the elevated UTC burden and the relevance
      of LS-specific surveillance.
  - reference: PMID:15962502
    reference_title: "[Transitional cell carcinoma of the upper urinary tract new concepts in management]."
    supports: SUPPORT
    snippet: 'Transitional cell carcinomas of the upper urinary tract (UUT-TCCs) are
      rare: they account for approximately 5% of all urothelial carcinomas. ... UUT-TCC
      occurs in 5% of patients with HNPCC.'
    explanation: The literature indicates that transitional cell carcinomas of
      the upper urinary tract are rare but occur in patients with Lynch syndrome
      (HNPCC), supporting the statement.
- category: Genitourinary
  frequency: OCCASIONAL
  name: Ovarian Cancer
  description: Epithelial ovarian cancer with increased lifetime risk in Lynch
    syndrome carriers, typically non-serous histology.
  phenotype_term:
    preferred_term: ovarian carcinoma
    term:
      id: MONDO:0005140
      label: ovarian carcinoma
  evidence:
  - reference: PMID:35435397
    reference_title: "Lynch syndrome: An unusal case of familial cancer unearthed."
    supports: SUPPORT
    snippet: There is an increased predisposition to cancers in the endometrium,
      colon, stomach, ovary, uterus, skin, kidney, and brain in patients of
      Lynch syndrome.
    explanation: This reference supports the association between Lynch Syndrome
      and ovarian cancer.
- category: Dermatologic
  frequency: OCCASIONAL
  name: Sebaceous Adenomas
  description: Sebaceous gland tumors associated with Muir-Torre syndrome, a
    phenotypic variant of Lynch syndrome.
  phenotype_term:
    preferred_term: sebaceous adenoma
    term:
      id: MONDO:0002375
      label: sebaceous adenoma
  notes: Muir-Torre variant of Lynch syndrome
  evidence:
  - reference: PMID:25427047
    reference_title: "Muir-Torre syndrome."
    supports: SUPPORT
    snippet: Muir-Torre syndrome (MTS) is a rare autosomal-dominant
      genodermatosis characterized by sebaceous neoplasms and one or more
      visceral malignancies. Sebaceous tumors include sebaceous adenoma and
      carcinoma, which may be solitary or multiple.
    explanation: The reference confirms that sebaceous adenomas are a part of
      the dermatologic manifestations in the Muir-Torre variant of Lynch
      syndrome.
  - reference: PMID:34023105
    reference_title: "Molecular Genetics of Sebaceous Neoplasia."
    supports: SUPPORT
    snippet: Sebaceous adenoma, sebaceoma, and a subset of cutaneous SC are
      frequently associated with defective DNA mismatch repair resulting from
      mutations in MLH1, MSH2, or MSH6. These tumors can be sporadic or
      associated with Muir-Torre syndrome.
    explanation: The reference supports the association of sebaceous adenomas
      with Lynch syndrome, particularly in the context of Muir-Torre syndrome.
  - reference: PMID:36418753
    reference_title: "Characterization of sebaceous and non-sebaceous cutaneous manifestations in patients with lynch syndrome: a systematic review."
    supports: SUPPORT
    snippet: >-
      The main skin lesions were: Sebaceous adenomas (43%), sebaceous carcinomas
      (27%), keratoacanthomas (16%), sebaceomas (13%), squamous cell carcinomas
      (23%), and basal cell carcinomas (10%).
    explanation: This systematic review confirms sebaceous adenoma as a common
      cutaneous Lynch-associated manifestation.
biochemical:
- name: Microsatellite Instability Testing
  notes: High microsatellite instability in tumors
  evidence:
  - reference: PMID:21970482
    reference_title: "Microsatellite instability and colorectal cancer."
    supports: SUPPORT
    snippet: About 15% of colorectal cancers are characterized by genomic
      microsatellite instability, and of these, about 1 in 5 (2%-4% overall) are
      due to Lynch syndrome...
    explanation: The reference discusses the correlation between Lynch syndrome
      and microsatellite instability in colorectal cancers, supporting that
      Lynch Syndrome can be biochemically identified via microsatellite
      instability testing.
  - reference: PMID:34611695
    reference_title: "A Simplified Protocol for Microsatellite Instability Evaluation in Iranian Patients at Risk for Lynch Syndrome."
    supports: SUPPORT
    snippet: The most important tumor characteristic of Lynch syndrome (LS) is
      microsatellite instability (MSI).
    explanation: This reference explicitly states that microsatellite
      instability is a critical characteristic of Lynch syndrome, supporting the
      statement.
  - reference: PMID:38466935
    reference_title: "Frameshift mutations in peripheral blood as a biomarker for surveillance of Lynch syndrome."
    supports: SUPPORT
    snippet: Lynch syndrome is a hereditary cancer predisposition syndrome
      caused by germline mutations in DNA mismatch repair genes, which lead to
      high microsatellite instability...
    explanation: The high microsatellite instability mentioned in this
      literature underscores the biochemical connection between Lynch syndrome
      and microsatellite instability testing.
  - reference: PMID:34630437
    reference_title: "Lynch Syndrome and MSI-H Cancers: From Mechanisms to \"Off-The-Shelf\" Cancer Vaccines."
    supports: SUPPORT
    snippet: Lynch syndrome - a hereditary cause of dMMR - confers increased
      lifetime risk of malignancy in different organs and tissues. These Lynch
      syndrome pathogenic alleles are widely present in humans...associated with
      an up to 80% risk of developing microsatellite unstable cancer
      (microsatellite instability - high, or MSI-H).
    explanation: The reference connects Lynch syndrome with a high risk of
      developing microsatellite instability-high (MSI-H) cancers, providing
      additional support for the statement.
- name: Immunohistochemistry
  notes: Absent mismatch repair proteins in tumors
  evidence:
  - reference: PMID:22067175
    reference_title: "Preoperative diagnosis of Lynch syndrome with DNA mismatch repair immunohistochemistry on a diagnostic biopsy."
    supports: SUPPORT
    snippet: DNA mismatch repair immunohistochemistry on tumor tissue is a
      simple, readily available, and cost-effective method of identifying
      patients with Lynch syndrome.
    explanation: The study explains that DNA mismatch repair
      immunohistochemistry is used for identifying Lynch syndrome, supporting
      the idea that biochemical tests involving immunohistochemistry can confirm
      the presence of absent mismatch repair proteins in tumors.
  - reference: PMID:19817892
    reference_title: "In Lynch syndrome adenomas, loss of mismatch repair proteins is related to an enhanced lymphocytic response."
    supports: SUPPORT
    snippet: In Lynch syndrome adenomas, loss of mismatch repair proteins is
      related to an enhanced lymphocytic response.
    explanation: The study directly correlates the loss of mismatch repair
      proteins with Lynch syndrome, supporting the use of immunohistochemistry
      to detect these biochemical changes.
  - reference: PMID:24333619
    reference_title: "Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors."
    supports: SUPPORT
    snippet: Lynch syndrome is caused by germline mutations in the mismatch
      repair (MMR) genes.
    explanation: This supports the statement by linking Lynch syndrome to
      mutations in mismatch repair genes, which can be identified using
      immunohistochemistry.
genetic:
- name: MLH1
  association: Germline Mutation
  inheritance:
  - name: Autosomal Dominant
    evidence:
    - reference: PMID:19466295
      reference_title: "Mismatch repair genes in Lynch syndrome: a review."
      supports: SUPPORT
      snippet: Lynch syndrome represents 1-7% of all cases of colorectal cancer
        and is an autosomal-dominant inherited cancer predisposition syndrome
        caused by germline mutations in deoxyribonucleic acid (DNA) mismatch
        repair genes.
      explanation: This supports autosomal dominant inheritance for Lynch
        syndrome caused by pathogenic mismatch repair variants including MLH1.
  evidence:
  - reference: PMID:28038733
    reference_title: "Genetic mutation risk calculation in Lynch syndrome inheritance: Evaluating the utility of the PREMM(1,2,6) model in Lyon: The first French study."
    supports: SUPPORT
    snippet: 'Lynch syndrome is due to germline mutations in mismatch repair genes:
      MLH1, MSH2, MSH6 and PMS2.'
    explanation: The reference directly indicates that Lynch syndrome is caused
      by germline mutations in the MLH1 gene among others.
  - reference: PMID:26886015
    reference_title: "Finding the needle in a haystack: identification of cases of Lynch syndrome with MLH1 epimutation."
    supports: SUPPORT
    snippet: Constitutional epimutation of the DNA mismatch repair gene, MLH1,
      represents a minor cause of Lynch syndrome.
    explanation: While the term 'epimutation' is used, it is within the context
      of the DNA mismatch repair gene MLH1 being a cause of Lynch syndrome.
- name: MSH2
  association: Germline Mutation
  evidence:
  - reference: PMID:29345684
    reference_title: "MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer."
    supports: PARTIAL
    snippet: Our data demonstrate that two LS genes, MSH6 and PMS2, are
      associated with an increased risk for breast cancer...
    explanation: While the MSH2 gene is mentioned, the research did not find a
      statistically significant association between MSH2 and breast cancer risk.
  - reference: PMID:25430799
    reference_title: "Genetic features of Lynch syndrome in the Israeli population."
    supports: SUPPORT
    snippet: Sixty-seven (59%) families had mutations in MSH2...
    explanation: This study reports a significant proportion of Lynch syndrome
      families with mutations in MSH2.
- name: MSH6
  association: Germline Mutation
  evidence:
  - reference: PMID:20028993
    reference_title: "Risks of Lynch syndrome cancers for MSH6 mutation carriers."
    supports: SUPPORT
    snippet: Germline mutations in MSH6 account for 10%-20% of Lynch syndrome
      colorectal cancers caused by hereditary DNA mismatch repair gene
      mutations.
    explanation: The study explicitly states that germline mutations in MSH6 are
      associated with Lynch Syndrome cancers.
  - reference: PMID:28038733
    reference_title: "Genetic mutation risk calculation in Lynch syndrome inheritance: Evaluating the utility of the PREMM(1,2,6) model in Lyon: The first French study."
    supports: SUPPORT
    snippet: 'Lynch syndrome is due to germline mutations in mismatch repair genes:
      MLH1, MSH2, MSH6 and PMS2.'
    explanation: The study identifies germline mutations in MSH6 as a cause of
      Lynch Syndrome.
  - reference: PMID:33516942
    reference_title: "Lynch syndrome and Muir-Torre phenotype associated with a recurrent variant in the 3'UTR of the MSH6 gene."
    supports: SUPPORT
    snippet: A MSH6 3'UTR variant (c.*23_26dup) was found in 13 unrelated
      families consulted for Lynch/Muir-Torre Syndrome.
    explanation: The study highlights that a specific variant of MSH6 is
      associated with families affected by Lynch Syndrome.
  - reference: PMID:25430799
    reference_title: "Genetic features of Lynch syndrome in the Israeli population."
    supports: SUPPORT
    snippet: Sixty-seven (59%) families had mutations in MSH2, 20 (18%) in MSH6,
      19 (17%) in MLH1 and 7 (6%) in PMS2.
    explanation: The study identifies families with Lynch Syndrome who have
      mutations in the MSH6 gene.
  - reference: PMID:33094597
    reference_title: "Coexistence of Constitutional Mismatch Repair Deficiency syndrome and Lynch syndrome in a family of seven : MSH6 mutation and childhood colorectal cancer - a case series."
    supports: SUPPORT
    snippet: Genetic analysis turned out positive for biallelic MSH6 mutations
      in the two girls, leading to CMMRD syndrome diagnosis. Both parents and
      two out of three alive siblings were diagnosed with Lynch syndrome.
    explanation: This informs about Lynch Syndrome diagnosis in individuals with
      MSH6 mutations.
- name: PMS2
  association: Germline Mutation
  evidence:
  - reference: PMID:18602922
    reference_title: "The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations."
    supports: SUPPORT
    snippet: PMS2 mutations contribute significantly to Lynch syndrome, but the
      penetrance for monoallelic mutation carriers appears to be lower than that
      for the other mismatch repair genes.
    explanation: This study confirms that germline mutations in PMS2 are
      associated with Lynch syndrome.
  - reference: PMID:24027009
    reference_title: "Inactivation of DNA mismatch repair by variants of uncertain significance in the PMS2 gene."
    supports: SUPPORT
    snippet: Lynch syndrome (LS) is a common cancer predisposition caused by an
      inactivating mutation in one of four DNA mismatch repair (MMR) genes.
      Frequently a variant of uncertain significance (VUS), rather than an
      obviously pathogenic mutation, is identified in one of these genes. The
      inability to define pathogenicity of such variants precludes targeted
      healthcare.
    explanation: The study discusses analyzing VUS in the MMR gene PMS2 for
      functional activity, indicating the association of PMS2 germline mutations
      with Lynch syndrome.
  - reference: PMID:37072247
    reference_title: "Pilot study of gene mutations associated with Lynch syndrome in Slovak patients with breast cancer."
    supports: SUPPORT
    snippet: As a result of our analysis, we managed to identify a mutation in
      the PMS2 gene in one patient's breast tumor tissue. The presence of this
      mutation indicates that the resulting cancer may be a consequence of LS.
    explanation: This study identifies a mutation of the PMS2 gene associated
      with Lynch syndrome, supporting the genetic association.
  - reference: PMID:25430799
    reference_title: "Genetic features of Lynch syndrome in the Israeli population."
    supports: SUPPORT
    snippet: We identified 54 different mutations; 13 of them are novel... Seven
      founder mutations were detected in 61/113 (54%) families... Gene
      distribution in the Israeli population is unique...7 (6%) in PMS2.
    explanation: PMS2 is one of the genes where germline mutations have been
      identified as causing Lynch syndrome.
- name: EPCAM
  association: Germline Mutation
  evidence:
  - reference: PMID:23411950
    reference_title: "[A novel genetic disorder of Lynch syndrome - EPCAM gene deletion]."
    supports: SUPPORT
    snippet: Germline mutations of 4 MMR genes, e.g., MLH1, MSH2, MSH6 and PMS2,
      had been identified as the cause of this disease, however, a novel
      mechanism, epigenetic inactivation of MSH2 gene due to hypermethylation of
      promotor region by the deletion of 3'part of epithelial cell adhesion
      molecule(EPCAM) gene which is located upstream of the MSH2 gene, has been
      reported in recent years.
  - reference: PMID:30461124
    reference_title: "EPCAM mutation update: Variants associated with congenital tufting enteropathy and Lynch syndrome."
    supports: SUPPORT
    snippet: Monoallelic deletions of the 3' end of EPCAM that silence the
      downstream gene, MSH2, cause a form of Lynch syndrome, which is a cancer
      predisposition syndrome associated with loss of DNA mismatch repair.
  - reference: PMID:37088804
    reference_title: "Lynch syndrome: influence of additional susceptibility variants on cancer risk."
    supports: SUPPORT
    snippet: 'Four EO cases stood out: two with POLE/POLD1 variants in the key exonuclease
      domain, one with a BMPR1A duplication and one with an EPCAM deletion.'
    explanation: EPCAM deletion is mentioned as one of the variants related to
      Lynch Syndrome.
environmental:
- name: Not Applicable
  notes: Lynch syndrome is primarily caused by inherited genetic mutations.
  evidence:
  - reference: PMID:29345160
    reference_title: "Inherited forms of bladder cancer: a review of Lynch syndrome and other inherited conditions."
    supports: REFUTE
    snippet: Environmental factors that play a role in the urothelial
      carcinogenesis have been well characterized. Current research is
      continuously exploring potential heritable forms of bladder cancer. Lynch
      syndrome is a well-known inheritable disease that increases the risk for a
      variety of cancers, including urothelial carcinomas.
    explanation: Lynch syndrome is described as an inherited disease, implying a
      genetic rather than environmental origin.
  - reference: PMID:31296810
    reference_title: "[Lynch Syndrome]."
    supports: REFUTE
    snippet: Lynch syndrome is caused by germline pathogenic variants in any of
      4 DNA mismatch repair(MMR)genes MLH1, MSH2, MSH6 or PMS2 and rarely in the
      non-MMR gene EPCAM, in which deletion of its last exon induce epigenetic
      silencing of MSH2.
    explanation: This indicates that Lynch syndrome is caused by genetic
      mutations, not by environmental factors.
treatments:
- name: Increased Cancer Surveillance
  description: Regular colonoscopies, endometrial biopsies, and other screening
    tests to detect cancers early.
  evidence:
  - reference: PMID:23176623
    reference_title: "Follow-up recommendations and risk-reduction initiatives for Lynch syndrome."
    supports: SUPPORT
    snippet: Some periodic screening strategies, such as colonoscopy, reduce the
      incidence and mortality of Lynch syndrome.
    explanation: Regular colonoscopies are highlighted as a beneficial screening
      strategy for Lynch Syndrome.
  - reference: PMID:31629885
    reference_title: "Cost-effectiveness of Active Identification and Subsequent Colonoscopy Surveillance of Lynch Syndrome Cases."
    supports: SUPPORT
    snippet: '...offering the FDRs with Lynch syndrome biennial colonoscopy surveillance
      was cost-effective...'
    explanation: The study emphasizes the importance of regular colonoscopy
      surveillance for those with Lynch syndrome.
  - reference: PMID:34698909
    reference_title: "Effectiveness of a surveillance program of upper endoscopy for upper gastrointestinal cancers in Lynch syndrome patients."
    supports: SUPPORT
    snippet: Lynch syndrome (LS) is the most common cause of hereditary
      colorectal cancer and is associated with an increased lifetime risk of
      gastric and duodenal cancers of 8-16% and 7%, respectively; therefore, we
      aim to describe an esophagogastroduodenoscopy (EGD) surveillance
      program...
    explanation: Endoscopies like EGD are implemented for cancer surveillance in
      LS patients, corroborating the need for ongoing screening tests.
  - reference: PMID:32875945
    reference_title: "Universal tumor screening for lynch syndrome: perspectives of patients regarding willingness and informed consent."
    supports: SUPPORT
    snippet: Universal tumor screening is a strategy to identify high-risk
      individuals by testing all CRC tumors for molecular features suggestive of
      Lynch Syndrome.
    explanation: Universal tumor screening further illustrates the importance of
      regular and early cancer detection methods for Lynch Syndrome patients.
  - reference: PMID:27241104
    reference_title: "Lynch Syndrome: Female Genital Tract Cancer Diagnosis and Screening."
    supports: SUPPORT
    snippet: This review discusses the rationales and relative merits of current
      Lynch syndrome screening tests for endometrial and ovarian cancers...
    explanation: Endometrial biopsies and other screening tests are discussed in
      the context of Lynch Syndrome, supporting the statement.
- name: Prophylactic Surgery
  description: Preventive removal of the colon, uterus, or ovaries may be
    considered in some cases.
  evidence:
  - reference: PMID:21287222
    reference_title: "Prophylactic surgery in Lynch syndrome."
    supports: SUPPORT
    snippet: Patients who are gene mutation carriers should receive counseling
      about colectomy, and if women, prophylactic hysterectomy and bilateral
      oophorectomy.
    explanation: The literature mentions counseling carriers about colectomy and
      prophylactic hysterectomy with bilateral oophorectomy, supporting that
      preventive removal of the colon, uterus, or ovaries may be considered.
  - reference: PMID:24495259
    reference_title: "Review of findings in prophylactic gynaecological specimens in Lynch syndrome with literature review and recommendations for grossing."
    supports: SUPPORT
    snippet: Prophylactic hysterectomy with bilateral salpingo-oophorectomy is
      being increasingly undertaken in patients with Lynch syndrome (LS).
    explanation: The literature indicates that prophylactic hysterectomy with
      bilateral salpingo-oophorectomy is a preventive measure undertaken in
      Lynch syndrome patients.
  - reference: PMID:31554630
    reference_title: "For Women, Lynch Syndrome Is About More than Colon Cancer."
    supports: SUPPORT
    snippet: for women with Lynch syndrome, the risks for gynecologic cancers
      pose an equal or greater risk than colorectal cancer.
    explanation: The literature outlines the significant risk of gynecologic
      cancers in women with Lynch syndrome, supporting the consideration of
      prophylactic surgery.
  - reference: PMID:27241104
    reference_title: "Lynch Syndrome: Female Genital Tract Cancer Diagnosis and Screening."
    supports: SUPPORT
    snippet: This review discusses the rationales and relative merits of current
      Lynch syndrome screening tests for endometrial and ovarian cancers.
    explanation: The discussion of screening tests implies the consideration of
      proactive measures, including prophylactic surgery, in managing the
      elevated cancer risks in Lynch syndrome.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Chemoprevention
  description: Aspirin or other NSAIDs may reduce the risk of colorectal cancer
    in Lynch syndrome patients.
  evidence:
  - reference: PMID:35328014
    reference_title: "Aspirin Colorectal Cancer Prevention in Lynch Syndrome: Recommendations in the Era of Precision Medicine."
    supports: SUPPORT
    snippet: Nonsteroidal anti-inflammatory drugs and, in particular, aspirin
      use, has been associated with reduced CRC risk in several studies...
    explanation: This study affirms that aspirin and other NSAIDs have been
      linked to a reduced risk of colorectal cancer in Lynch syndrome patients.
  - reference: PMID:11854387
    reference_title: "Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues."
    supports: PARTIAL
    snippet: Numerous experimental, epidemiologic, and clinical studies suggest
      that nonsteroidal anti-inflammatory drugs (NSAIDs), particularly the
      highly selective cyclooxygenase (COX)-2 inhibitors, have promise as
      anticancer agents...
    explanation: The study indicates a potential for NSAIDs in cancer
      prevention, including colorectal cancer, but notes that unresolved
      questions about safety and efficacy limit clinical application.
  - reference: PMID:36202092
    reference_title: "An Aspirin a Day: New Pharmacological Developments and Cancer Chemoprevention."
    supports: SUPPORT
    snippet: '...multiple pharmacological, clinical, and epidemiologic studies suggest
      that aspirin can prevent certain cancers...'
    explanation: This study supports the role of aspirin in cancer prevention,
      including colorectal cancer, though mentions variable effects depending on
      the tissue and disease context.
  - reference: PMID:34798982
    reference_title: "Chemoprevention Considerations in Patients with Hereditary Colorectal Cancer Syndromes."
    supports: SUPPORT
    snippet: Secondary prevention of colorectal neoplasia with chemoprevention
      is long-studied area of research and clinical use in patients with the 2
      most common hereditary colorectal cancer syndromes including Lynch
      syndrome and familial adenomatous polyposis
    explanation: This study notes the history and research supporting
      chemoprevention, including with NSAIDs, for hereditary colorectal cancer
      syndromes like Lynch syndrome.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: acetylsalicylic acid
      term:
        id: CHEBI:15365
        label: acetylsalicylic acid
- name: Targeted Therapies
  description: Immunotherapies like checkpoint inhibitors may be effective for
    treating some Lynch syndrome-related cancers.
  evidence:
  - reference: PMID:37625240
    reference_title: "Efficacy of PD-1 inhibitors for colorectal cancer and polyps in Lynch syndrome patients."
    supports: SUPPORT
    snippet: PD-1 inhibitors are highly effective for dMMR and MSI-H LS CRCs,
      but not for pMMR or MSS LS CRCs or mucinous/signet-ring cell CRC.
    explanation: This study demonstrates the efficacy of PD-1 inhibitors, a type
      of immune checkpoint inhibitor, for treating Lynch syndrome (LS) patients
      with colorectal cancers characterized by deficient mismatch repair (dMMR)
      or high microsatellite instability (MSI-H).
  - reference: PMID:34224739
    reference_title: "Recurrent Frameshift Neoantigen Vaccine Elicits Protective Immunity With Reduced Tumor Burden and Improved Overall Survival in a Lynch Syndrome Mouse Model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We identified 4 shared FSP neoantigens ... Using VCMsh2 mice, which
      have a conditional knockout of Msh2 in the intestinal tract and develop
      intestinal cancer, we showed vaccination with a combination of only 4 FSPs
      significantly increased FSP-specific adaptive immunity, reduced intestinal
      tumor burden, and prolonged overall survival.
    explanation: This study indicates that immunotherapies, specifically FSP
      neoantigen vaccines, can be effective in reducing the tumor burden and
      improving survival in Lynch syndrome mouse models.
  - reference: PMID:30027543
    reference_title: "Lynch syndrome - cancer pathways, heterogeneity and immune escape."
    supports: SUPPORT
    snippet: Immunotherapies are an active field of research for MSI cancers and
      their potential use for cancer therapy for both sporadic and LS MSI
      cancers is discussed.
    explanation: This reference discusses ongoing research into immunotherapies
      for MSI cancers, including those associated with Lynch syndrome.
  - reference: PMID:37845474
    reference_title: "Neoplasia risk in patients with Lynch syndrome treated with immune checkpoint blockade."
    supports: PARTIAL
    snippet: Metastatic and localized mismatch repair-deficient (dMMR) tumors
      are exquisitely sensitive to immune checkpoint blockade (ICB).
    explanation: While ICB is effective for treating dMMR tumors in Lynch
      syndrome patients, it does not eliminate the risk of new neoplasia
      development, highlighting the need for continued surveillance.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
review_notes: Lynch syndrome is caused by inherited mutations in mismatch repair
  genes, leading to a very high lifetime risk of colorectal and endometrial
  cancers. Risks of other cancers like stomach, ovary, and urinary tract are
  also elevated. Screening and prophylactic surgery can reduce cancer incidence
  and mortality.
datasets:
# French CIT colon cancer cohort with MSI status
- accession: geo:GSE39582
  title: Gene expression Classification of Colon Cancer defines six molecular
    subtypes with distinct clinical, molecular and survival characteristics
    [Expression]
  description: >-
    Large French multicenter cohort (Cartes d'Identité des Tumeurs program)
    with 566 colon tumor samples and 19 non-tumoral colorectal mucosa samples
    (585 total) including MSI status annotation.
    Contains 71 MSI-high and 439 MSS samples, useful for studying
    Lynch syndrome-associated molecular signatures.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_types:
  - preferred_term: colon tumor tissue
    term:
      id: UBERON:0001155
      label: colon
    tissue_term:
      preferred_term: colon
      term:
        id: UBERON:0001155
        label: colon
  sample_count: 585
  conditions:
  - MSI-high colon cancer
  - MSS colon cancer
  - non-tumoral colorectal mucosa
  platform: Affymetrix Human Genome U133 Plus 2.0 Array
  publication: PMID:23700391
  evidence:
  - reference: PMID:23700391
    reference_title: "Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value."
    supports: SUPPORT
    snippet: 566 samples fulfilled RNA quality requirements. Unsupervised
      consensus hierarchical clustering applied to gene expression data from a
      discovery subset of 443 CC samples identified six molecular subtypes.
    explanation: This supports the cohort composition and molecular subtype
      characterization captured in this dataset entry.
  notes: >-
    Identifies six molecular subtypes with distinct survival outcomes.
    MSI status allows identification of Lynch-like tumors and study
    of immune infiltration patterns.

# Moffitt colon cancer validation cohort
- accession: geo:GSE17536
  title: Metastasis Gene Expression Profile Predicts Recurrence and Death in
    Colon Cancer Patients (Moffitt Samples)
  description: >-
    Independent validation cohort of 177 colon cancer samples from
    Moffitt Cancer Center with clinical outcome data including
    metastasis risk and survival information.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_types:
  - preferred_term: colon tumor tissue
    term:
      id: UBERON:0001155
      label: colon
    tissue_term:
      preferred_term: colon
      term:
        id: UBERON:0001155
        label: colon
  sample_count: 177
  conditions:
  - colon cancer (various stages)
  publication: PMID:19914252
  evidence:
  - reference: PMID:19914252
    reference_title: "Experimentally derived metastasis gene expression profile predicts recurrence and death in patients with colon cancer."
    supports: SUPPORT
    snippet: This phase 1, exploratory biomarker study used 55 patients with
      colorectal cancer from Vanderbilt Medical Center (VMC) as the training
      dataset and 177 patients from the Moffitt Cancer Center as the independent
      dataset.
    explanation: This directly supports the Moffitt cohort sample count and
      study context represented in this dataset entry.
  notes: >-
    Used with GSE39582 for validation of molecular classifiers.
    Contains stage information useful for prognostic analysis

# Lynch syndrome premalignant lesion RNA-seq cohort
- accession: geo:GSE106500
  title: Immune Profiling of Premalignant Lesions in Patients with Lynch
    Syndrome
  description: >-
    RNA-seq cohort of colorectal adenomas from Lynch syndrome patients,
    with comparator familial adenomatous polyposis adenomas, used for
    transcriptomic immune profiling of premalignant lesions.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_types:
  - preferred_term: colorectal adenoma tissue
    term:
      id: UBERON:0001155
      label: colon
    tissue_term:
      preferred_term: colon
      term:
        id: UBERON:0001155
        label: colon
  sample_count: 24
  conditions:
  - Lynch syndrome colorectal adenoma
  - familial adenomatous polyposis colorectal adenoma
  platform: Illumina HiSeq 2000
  publication: PMID:29710228
  evidence:
  - reference: PMID:29710228
    reference_title: "Immune Profiling of Premalignant Lesions in Patients With Lynch Syndrome."
    supports: SUPPORT
    snippet: Whole-genome transcriptomic analysis using next-generation
      sequencing was performed in colorectal polyps and carcinomas of patients
      with LS.
    explanation: This directly supports transcriptomic sequencing in Lynch
      syndrome colorectal premalignant/tumor lesions relevant to this GEO
      cohort.
  notes: >-
    Focuses on early lesion immune activation and checkpoint biology in LS,
    useful for mechanistic chemoprevention and interception studies.

# Lynch syndrome urothelial carcinoma molecular subtype cohort
- accession: geo:GSE104922
  title: Molecular subtype classification of urothelial carcinoma in Lynch
    syndrome
  description: >-
    Microarray cohort of Lynch syndrome-associated urothelial cancers from
    bladder and upper urinary tract, profiled for molecular subtype mapping,
    MSI status, and clinicopathologic associations.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_types:
  - preferred_term: urinary bladder tumor tissue
    term:
      id: UBERON:0001255
      label: urinary bladder
    tissue_term:
      preferred_term: urinary bladder
      term:
        id: UBERON:0001255
        label: urinary bladder
  - preferred_term: upper urinary tract tumor tissue
    term:
      id: UBERON:0011143
      label: upper urinary tract
    tissue_term:
      preferred_term: upper urinary tract
      term:
        id: UBERON:0011143
        label: upper urinary tract
  sample_count: 41
  conditions:
  - Lynch syndrome urothelial carcinoma
  - upper urinary tract urothelial carcinoma
  - bladder urothelial carcinoma
  platform: Affymetrix Human Gene 1.0 ST Array
  publication: PMID:29791078
  evidence:
  - reference: PMID:29791078
    reference_title: "Molecular subtype classification of urothelial carcinoma in Lynch syndrome."
    supports: SUPPORT
    snippet: Whole-genome mRNA expression profiles of 41 tumors and
      immunohistochemical stainings against FGFR3, KRT5, CCNB1, RB1, and CDKN2A
      (p16) of 37 tumors from patients with Lynch syndrome were generated.
    explanation: This supports both the cohort scale and molecular profiling
      design represented in this Lynch-associated urothelial dataset.
  notes: >-
    Enables analysis of urinary tract phenotypes in LS and comparison to
    sporadic urothelial molecular subtypes.

# Hereditary nonpolyposis colorectal cancer expression cohort (LS vs FCCTX)
- accession: geo:GSE36335
  title: Distinct tumorigenic pathways within hereditary nonpolyposis colorectal
    cancer
  description: >-
    FFPE colorectal cancer expression cohort spanning Lynch syndrome,
    familial colorectal cancer type X (FCCTX), and sporadic CRC,
    designed to identify hereditary pathway-level differences.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_types:
  - preferred_term: colorectal carcinoma tissue
    term:
      id: UBERON:0001155
      label: colon
    tissue_term:
      preferred_term: colon
      term:
        id: UBERON:0001155
        label: colon
  sample_count: 132
  conditions:
  - Lynch syndrome colorectal cancer
  - familial colorectal cancer type X
  - sporadic colorectal cancer
  platform: Illumina HumanHT-12 WG-DASL V4.0 R2 expression beadchip
  publication: PMID:23951239
  evidence:
  - reference: PMID:23951239
    reference_title: "Distinct gene expression signatures in lynch syndrome and familial colorectal cancer type x."
    supports: SUPPORT
    snippet: The 18 k whole-genome c-DNA-mediated annealing, selection,
      extension, and ligation (WG-DASL) assay was applied to 123 colorectal
      cancers, including 39 Lynch syndrome tumors and 37 FCCTX tumors.
    explanation: This supports the hereditary colorectal expression profiling
      framework and LS-relevant tumor subset captured in this GEO series.
  notes: >-
    Useful for distinguishing LS-specific transcriptional programs from FCCTX and
    sporadic CRC backgrounds.

disease_term:
  preferred_term: Lynch syndrome
  term:
    id: MONDO:0005835
    label: Lynch syndrome
references:
- reference: DOI:10.1038/s41431-024-01550-w
  title: 'Identification of people with Lynch syndrome from those presenting with
    colorectal cancer in England: baseline analysis of the diagnostic pathway'
  findings: []
- reference: DOI:10.1038/s41591-024-02942-7
  title: 'Nivolumab for mismatch-repair-deficient or hypermutated gynecologic cancers:
    a phase 2 trial with biomarker analyses'
  findings: []
- reference: DOI:10.1200/po.22.00675
  title: Prevalence and Clinical Implications of Mismatch Repair-Proficient
    Colorectal Cancer in Patients With Lynch Syndrome
  findings: []
- reference: DOI:10.1200/po.23.00332
  title: Microsatellite Instability Is Insufficiently Used as a Biomarker for
    Lynch Syndrome Testing in Clinical Practice
  findings: []
- reference: DOI:10.32604/or.2025.063951
  title: 'Lynch syndrome and colorectal cancer: A review of current perspectives in
    molecular genetics and clinical strategies'
  findings: []
- reference: DOI:10.3389/or.2025.1549416
  title: 'A brief review of Lynch syndrome: understanding the dual cancer risk between
    endometrial and colorectal cancer'
  findings: []
- reference: DOI:10.3390/cancers16050849
  title: 'Lynch Syndrome: From Multidisciplinary Management to Precision Prevention'
  findings: []
- reference: DOI:10.3390/ijms26094394
  title: Deficient Mismatch Repair and Microsatellite Instability in Solid
    Tumors
  findings: []