◆

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.

◈

Mechanistic Hypotheses

1

Canonical Mismatch Repair Loss / MSI Carcinogenesis Model

canonical_mmr_msi_carcinogenesis_model CANONICAL

Lynch syndrome is caused by germline heterozygous loss-of-function variants in the DNA mismatch repair genes MLH1, MSH2, MSH6, or PMS2, or by EPCAM 3' deletions that silence MSH2 in epithelial tissue. Somatic biallelic MMR inactivation ('second hit') in intestinal, endometrial, and other epithelium produces microsatellite instability (MSI-H), accumulating insertion/deletion mutations at short tandem repeats and frameshift mutations in tumor suppressor genes (TGFBR2, BAX, MSH3) that drive colorectal, endometrial, ovarian, gastric, and urothelial carcinogenesis. The accelerated adenoma-carcinoma sequence in MMR-deficient colon (versus the Vogelstein chromosomal-instability path in FAP) explains the early-onset, right-sided, often poorly differentiated phenotype. MSI testing and IHC for MLH1/MSH2/MSH6/PMS2 are now standard tumor screening modalities. Immune checkpoint blockade (pembrolizumab, nivolumab) is highly effective in MSI-H tumors, corroborating that hypermutation-driven neoantigen load is mechanistically coupled to MMR loss and validates the MSI carcinogenesis axis of the canonical model.

Retained as CANONICAL with important qualifiers. The 2026 falcon hypothesis-search report (kb/hypotheses/Lynch_Syndrome/canonical_mmr_msi_carcinogenesis_model; openscientist timed out at 3600s) finds SUPPORTED. The germline MMR etiology, requirement for biallelic somatic inactivation in tumors/crypts, MSI-H / hypermutation phenotype, and predictive value of MSI/dMMR for immune checkpoint blockade (ICI) — particularly pembrolizumab, nivolumab + ipilimumab, dostarlimab — are strongly supported and remain standard-of-care in diagnostics and therapy selection. Three key qualifications: (1) phenocopies and etiologic heterogeneity — sporadic MSI via MLH1 hypermethylation ± BRAF V600E and 'double-somatic MMR' tumors can mimic LS biology without germline LS, requiring BRAF/MLH1-methylation reflex testing; (2) diagnostic discordance / subtype nuance — universal tumor screening (UTS) can miss LS and dMMR can be functionally present with retained IHC expression; atypical patterns require reflex MSI-PCR / NGS per modern algorithms; (3) mechanism expansion beyond coding frameshifts — noncoding MSI (splicing-affecting intronic microsatellites) occurs very early in dMMR crypts and may contribute to initiation BEFORE classical coding driver accumulation, refining the canonical adenoma-carcinoma sequence. EPCAM 3' deletions silencing MSH2 in epithelial tissue extend the canonical genetic etiology to non-MMR germline causes.

Deep research

Falcon citations 51 citations 2026-05-25T12:49:55.107797

Show evidence (1 reference)

PMID:19466295 SUPPORT Other

"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."

Existing canonical mechanism citation in the dismech knowledge base, used as the seed for the hypothesis-search deep-research run.

⚙

Pathophysiology

5

DNA Mismatch Repair Deficiency

Mutations in mismatch repair genes lead to an accumulation of DNA replication errors.

colonic epithelial cell CL:0011108 endometrial epithelial cell CL:0002656

mismatch repair complex GO:0032300

mismatch repair GO:0006298 ↓ DECREASED DNA-templated DNA replication maintenance of fidelity GO:0045005 ↓ DECREASED DNA damage response GO:0006974 ⚠ ABNORMAL

nucleoplasm GO:0005654

nucleus GO:0005634

Downstream

Microsatellite Instability Loss of mismatch repair causes unstable microsatellite repeats and increased insertion-deletion burden.

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 CL:0011108 endometrial epithelial cell CL:0002656

DNA-templated DNA replication maintenance of fidelity GO:0045005 ↓ DECREASED

colon UBERON:0001155 endometrium UBERON:0001295

Downstream

Accelerated Tumor Development MSI-associated coding frameshift mutations increase oncogenic transformation risk.

Neoantigen Generation and Immune Activation Frameshifted proteins generate immunogenic neoepitopes.

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 CL:0011108 endometrial epithelial cell CL:0002656

cell population proliferation GO:0008283 ↑ INCREASED

colon UBERON:0001155 endometrium UBERON:0001295

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 CL:0000625

antigen processing and presentation of peptide antigen via MHC class I GO:0002474 ↑ INCREASED type I interferon-mediated signaling pathway GO:0060337 ↑ INCREASED T cell mediated cytotoxicity directed against tumor cell target GO:0002419 ↑ INCREASED

colon UBERON:0001155 endometrium UBERON:0001295

Downstream

Immune Checkpoint Blockade Sensitivity High neoantigen load and cytotoxic T-cell infiltration create therapeutic vulnerability to PD-1 blockade.

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 GO:0002419 ↑ 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

●

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

6

MLH1 (Germline Mutation)

Autosomal Dominant

Show evidence (3 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.

CGGV:assertion_24c5d3f4-2bb6-4beb-a781-52bd6962ca41-2022-06-20T170000.000Z SUPPORT Other

ClinGen classifies the MLH1-Lynch syndrome gene-disease relationship as definitive with autosomal dominant inheritance.

MSH2 (Germline Mutation)

Show evidence (3 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.

CGGV:assertion_0f3acd9a-e2e5-498a-8974-399969ffa2d1-2022-06-20T170000.000Z SUPPORT Other

ClinGen classifies the MSH2-Lynch syndrome gene-disease relationship as definitive with autosomal dominant inheritance.

MSH6 (Germline Mutation)

Show evidence (6 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.

+ 3 more references

PMS2 (Germline Mutation)

Show evidence (5 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.

+ 2 more references

EPCAM (Germline Mutation)

Show evidence (4 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.

+ 1 more reference

RPS20 (Pathogenic Variants)

Gene: RPS20 hgnc:10405

Show evidence (1 reference)

CGGV:assertion_258ec9c5-12bb-4d8b-9bc2-d5747b52660c-2024-03-22T170000.000Z SUPPORT Other

ClinGen classifies the RPS20-Lynch syndrome gene-disease relationship as limited with autosomal dominant inheritance.

💊

Medical Actions

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: chemoprevention Ontology label: Pharmacotherapy NCIT:C15986

Agent: acetylsalicylic acid CHEBI:15365

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: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

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.

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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.

{ }

Source YAML

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name: Lynch Syndrome
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-04-28T16:00:00Z'
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.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_mmr_msi_carcinogenesis_model
  hypothesis_label: Canonical Mismatch Repair Loss / MSI Carcinogenesis Model
  status: CANONICAL
  description: >-
    Lynch syndrome is caused by germline heterozygous loss-of-function variants in the DNA mismatch
    repair genes MLH1, MSH2, MSH6, or PMS2, or by EPCAM 3' deletions that silence MSH2 in epithelial
    tissue. Somatic biallelic MMR inactivation ('second hit') in intestinal, endometrial, and other
    epithelium produces microsatellite instability (MSI-H), accumulating insertion/deletion mutations at
    short tandem repeats and frameshift mutations in tumor suppressor genes (TGFBR2, BAX, MSH3) that
    drive colorectal, endometrial, ovarian, gastric, and urothelial carcinogenesis. The accelerated
    adenoma-carcinoma sequence in MMR-deficient colon (versus the Vogelstein chromosomal-instability
    path in FAP) explains the early-onset, right-sided, often poorly differentiated phenotype. MSI
    testing and IHC for MLH1/MSH2/MSH6/PMS2 are now standard tumor screening modalities. Immune
    checkpoint blockade (pembrolizumab, nivolumab) is highly effective in MSI-H tumors, corroborating
    that hypermutation-driven neoantigen load is mechanistically coupled to MMR loss and validates the
    MSI carcinogenesis axis of the canonical model.
  notes: >-
    Retained as CANONICAL with important qualifiers.
    The 2026 falcon hypothesis-search report
    (kb/hypotheses/Lynch_Syndrome/canonical_mmr_msi_carcinogenesis_model;
    openscientist timed out at 3600s) finds SUPPORTED. The
    germline MMR etiology, requirement for biallelic somatic
    inactivation in tumors/crypts, MSI-H / hypermutation
    phenotype, and predictive value of MSI/dMMR for immune
    checkpoint blockade (ICI) — particularly pembrolizumab,
    nivolumab + ipilimumab, dostarlimab — are strongly supported
    and remain standard-of-care in diagnostics and therapy
    selection. Three key qualifications: (1) phenocopies and
    etiologic heterogeneity — sporadic MSI via MLH1
    hypermethylation ± BRAF V600E and 'double-somatic MMR' tumors
    can mimic LS biology without germline LS, requiring
    BRAF/MLH1-methylation reflex testing; (2) diagnostic
    discordance / subtype nuance — universal tumor screening
    (UTS) can miss LS and dMMR can be functionally present with
    retained IHC expression; atypical patterns require reflex
    MSI-PCR / NGS per modern algorithms; (3) mechanism expansion
    beyond coding frameshifts — noncoding MSI (splicing-affecting
    intronic microsatellites) occurs very early in dMMR crypts
    and may contribute to initiation BEFORE classical coding
    driver accumulation, refining the canonical adenoma-carcinoma
    sequence. EPCAM 3' deletions silencing MSH2 in epithelial
    tissue extend the canonical genetic etiology to non-MMR
    germline causes.
  evidence:
  - reference: PMID:19466295
    reference_title: "Mismatch repair genes in Lynch syndrome: a review."
    supports: SUPPORT
    evidence_source: OTHER
    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: >
      Existing canonical mechanism citation in the dismech
      knowledge base, used as the seed for the hypothesis-search
      deep-research run.
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.
  - reference: CGGV:assertion_24c5d3f4-2bb6-4beb-a781-52bd6962ca41-2022-06-20T170000.000Z
    reference_title: "MLH1 / Lynch syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MLH1 | HGNC:7127 | Lynch syndrome | MONDO:0005835 | AD | Definitive"
    explanation: ClinGen classifies the MLH1-Lynch syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- 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.
  - reference: CGGV:assertion_0f3acd9a-e2e5-498a-8974-399969ffa2d1-2022-06-20T170000.000Z
    reference_title: "MSH2 / Lynch syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MSH2 | HGNC:7325 | Lynch syndrome | MONDO:0005835 | AD | Definitive"
    explanation: ClinGen classifies the MSH2-Lynch syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- 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.
  - reference: CGGV:assertion_bc6e042d-74ad-42fc-9638-7f53f8bc32f9-2023-07-05T170000.000Z
    reference_title: "MSH6 / Lynch syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MSH6 | HGNC:7329 | Lynch syndrome | MONDO:0005835 | AD | Definitive"
    explanation: ClinGen classifies the MSH6-Lynch syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- 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.
  - reference: CGGV:assertion_213ba61e-a4a5-4e4f-945d-f0fef691a9ba-2022-12-30T180000.000Z
    reference_title: "PMS2 / Lynch syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PMS2 | HGNC:9122 | Lynch syndrome | MONDO:0005835 | AD | Definitive"
    explanation: ClinGen classifies the PMS2-Lynch syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- 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.
  - reference: CGGV:assertion_3c071c7e-ba5c-46c7-b46b-fee6acf3a43f-2022-06-20T170000.000Z
    reference_title: "EPCAM / Lynch syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "EPCAM | HGNC:11529 | Lynch syndrome | MONDO:0005835 | AD | Definitive"
    explanation: ClinGen classifies the EPCAM-Lynch syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: RPS20
  gene_term:
    preferred_term: RPS20
    term:
      id: hgnc:10405
      label: RPS20
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_258ec9c5-12bb-4d8b-9bc2-d5747b52660c-2024-03-22T170000.000Z
    reference_title: "RPS20 / Lynch syndrome (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RPS20 | HGNC:10405 | Lynch syndrome | MONDO:0005835 | AD | Limited"
    explanation: ClinGen classifies the RPS20-Lynch syndrome gene-disease relationship as limited with autosomal dominant inheritance.
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: chemoprevention
    term:
      id: NCIT:C15986
      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: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
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: []

📚

References & Deep Research

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