Microsatellite instability-high (MSI-H) colorectal cancer is a molecularly defined subtype characterized by deficient DNA mismatch repair (dMMR), resulting in hypermutation and high tumor mutational burden (TMB). This occurs through germline mutations in MMR genes (Lynch syndrome) or sporadic MLH1 promoter hypermethylation. MSI-H tumors have distinct clinical features including proximal colon predominance, mucinous histology, and tumor-infiltrating lymphocytes. The high neoantigen load makes these tumors exquisitely sensitive to immune checkpoint inhibitors, with pembrolizumab now approved as first-line therapy for metastatic MSI-H colorectal cancer.
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name: MSI-High Colorectal Cancer
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-05-11T02:45:15Z'
description: >-
Microsatellite instability-high (MSI-H) colorectal cancer is a molecularly defined
subtype
characterized by deficient DNA mismatch repair (dMMR), resulting in hypermutation
and high
tumor mutational burden (TMB). This occurs through germline mutations in MMR genes
(Lynch
syndrome) or sporadic MLH1 promoter hypermethylation. MSI-H tumors have distinct
clinical
features including proximal colon predominance, mucinous histology, and tumor-infiltrating
lymphocytes. The high neoantigen load makes these tumors exquisitely sensitive to
immune
checkpoint inhibitors, with pembrolizumab now approved as first-line therapy for
metastatic
MSI-H colorectal cancer.
categories:
- Gastrointestinal Cancer
- Colorectal Cancer
- Molecularly Defined Cancer
parents:
- colorectal adenocarcinoma
external_assertions:
- name: CIViC MSI High ipilimumab/nivolumab sensitivity evidence item 12561
source: CIViC
assertion_type: accepted_evidence_item
external_id: CIVIC_EID:12561
url: https://civicdb.org/links/evidence_items/12561
description: >-
CIViC accepted evidence item linking MSI High colorectal cancer to
sensitivity/response to the ipilimumab/nivolumab regimen.
notes: >-
01-May-2026 CIViC accepted evidence item: molecular_profile="MSI High";
disease="Colorectal Cancer"; evidence_type=Predictive; evidence_level=A;
significance=Sensitivity/Response; therapy=Ipilimumab/Nivolumab Regimen;
citation_id=PMID:39602630.
evidence:
- reference: CIVIC_EID:12561
reference_title: "MSI High / Colorectal Cancer (Predictive Sensitivity/Response)"
supports: SUPPORT
evidence_source: OTHER
snippet: nivolumab plus ipilimumab significantly improved progression-free survival versus investigator’s choice of chemotherapy
explanation: CIViC records an accepted predictive sensitivity evidence item for MSI-high colorectal cancer and ipilimumab/nivolumab.
- name: CIViC MSI High ipilimumab/nivolumab sensitivity evidence item 12562
source: CIViC
assertion_type: accepted_evidence_item
external_id: CIVIC_EID:12562
url: https://civicdb.org/links/evidence_items/12562
description: >-
CIViC accepted evidence item linking MSI High colorectal cancer to
sensitivity/response to the ipilimumab/nivolumab regimen.
notes: >-
01-May-2026 CIViC accepted evidence item: molecular_profile="MSI High";
disease="Colorectal Cancer"; evidence_type=Predictive; evidence_level=A;
significance=Sensitivity/Response; therapy=Ipilimumab/Nivolumab Regimen;
citation_id=PMID:39874977.
evidence:
- reference: CIVIC_EID:12562
reference_title: "MSI High / Colorectal Cancer (Predictive Sensitivity/Response)"
supports: SUPPORT
evidence_source: OTHER
snippet: nivolumab plus ipilimumab significantly improved progression-free survival versus nivolumab monotherapy across all treatment lines
explanation: CIViC records an accepted predictive sensitivity evidence item for MSI-high colorectal cancer and ipilimumab/nivolumab.
has_subtypes:
- name: Lynch Syndrome-Associated MSI-H CRC
description: >-
Hereditary MSI-H colorectal cancer caused by germline mutations in MMR genes (MLH1,
MSH2,
MSH6, PMS2) or EPCAM deletions affecting MSH2. Accounts for approximately 3% of
all CRC.
Younger age at onset, right-sided predominance, and risk of synchronous/metachronous
cancers.
evidence:
- reference: PMID:15340260
reference_title: "Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer."
supports: PARTIAL
snippet: >-
Colorectal cancers resulting from defective DNA mismatch repair can occur in
both
hereditary non-polyposis colon cancer (HNPCC) and in the sporadic setting.
explanation: >-
Study confirms that MSI-H colorectal cancers can arise from hereditary (HNPCC/Lynch
syndrome) or sporadic causes.
mappings:
ncit_mappings:
- term:
id: NCIT:C8494
label: Lynch Syndrome
mapping_predicate: skos:closeMatch
mapping_source: NCIT
mapping_justification: NCIT provides a closely related hereditary syndrome term for the germline etiology underlying this MSI-H CRC subtype.
- name: Sporadic MSI-H CRC
description: >-
Non-hereditary MSI-H colorectal cancer caused by biallelic MLH1 promoter hypermethylation,
often with concurrent BRAF V600E mutation. Typically occurs in older patients,
predominantly
female, with right-sided tumors.
evidence:
- reference: PMID:15340260
reference_title: "Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer."
supports: PARTIAL
snippet: >-
BRAF mutations were detected in 74% of sporadic tumours but none of the HNPCC
cancers tested.
explanation: >-
Study demonstrates that BRAF mutations distinguish sporadic MSI-H CRC from Lynch
syndrome-associated tumors.
pathophysiology:
- name: DNA Mismatch Repair Deficiency
description: >-
Loss of MMR protein function (MLH1, MSH2, MSH6, or PMS2) impairs the recognition
and repair
of DNA replication errors. The MMR system normally corrects base-base mismatches
and
insertion/deletion loops at microsatellite sequences. Deficiency leads to accumulation
of
thousands of somatic mutations.
evidence:
- reference: PMID:41113075
reference_title: "Spontaneous colonic transection following pathologic complete response to pembrolizumab in high microsatellite instability colorectal cancer: A case report and review of literature."
supports: PARTIAL
snippet: High microsatellite instability (MSI-H) colorectal cancer (CRC), caused by deficient mismatch repair, accounts for about 15% of all CRC cases and is more common in right-sided tumors.
explanation: This abstract explicitly links MSI-H CRC to deficient mismatch repair, supporting the core disease mechanism described.
cell_types:
- preferred_term: colon epithelial cell
term:
id: CL:0011108
label: colon epithelial cell
biological_processes:
- preferred_term: mismatch repair
modifier: DECREASED
term:
id: GO:0006298
label: mismatch repair
downstream:
- target: Microsatellite Instability
description: Impaired MMR leads to length alterations at microsatellite repeat sequences
- target: Hypermutation and High TMB
description: Accumulated replication errors result in high somatic mutation burden
- name: Microsatellite Instability
description: >-
Microsatellites are repetitive DNA sequences highly susceptible to replication
errors.
Without functional MMR, these sequences accumulate insertions and deletions, detectable
as length variations (instability) compared to normal tissue. MSI-H is defined
as
instability at two or more of five standard markers.
evidence:
- reference: PMID:36115290
reference_title: "Deficient mismatch repair/microsatellite unstable colorectal cancer: Diagnosis, prognosis and treatment."
supports: PARTIAL
snippet: "Microsatellite unstable (MSI) colorectal cancers (CRCs) are due to DNA mismatch repair (MMR) deficiency"
explanation: "Abstract links MSI CRC to MMR deficiency, supporting the MSI mechanism."
locations:
- preferred_term: colon
term:
id: UBERON:0001155
label: colon
downstream:
- target: Frameshift Mutations in Tumor Suppressors
description: Microsatellite instability causes frameshift mutations in coding sequences
- name: Hypermutation and High TMB
description: >-
MSI-H tumors accumulate 10-100 times more somatic mutations than microsatellite
stable
tumors, resulting in tumor mutational burden often exceeding 10-20 mutations per
megabase.
This creates abundant neoantigens derived from mutant peptides presented on MHC
molecules.
evidence:
- reference: PMID:36115290
reference_title: "Deficient mismatch repair/microsatellite unstable colorectal cancer: Diagnosis, prognosis and treatment."
supports: PARTIAL
snippet: "The pathogenic alterations of MMR genes lead to the accumulation of frequent somatic mutational events"
explanation: "Abstract notes frequent somatic mutational events from MMR alterations, consistent with hypermutation."
downstream:
- target: Neoantigen-Driven Immune Response
description: High mutation load generates abundant immunogenic neoantigens
- name: Frameshift Mutations in Tumor Suppressors
description: >-
Coding microsatellites in tumor suppressor genes (TGFbetaRII, BAX, ACVR2, IGF2R)
accumulate
frameshift mutations, inactivating their tumor suppressive functions. TGFbetaRII
frameshift
is particularly common, disrupting TGF-beta growth inhibition.
biological_processes:
- preferred_term: cell population proliferation
modifier: INCREASED
term:
id: GO:0008283
label: cell population proliferation
- name: Neoantigen-Driven Immune Response
conforms_to: "immune_checkpoint_blockade#Anti-Tumor T Cell Response"
description: >-
The high neoantigen burden in MSI-H tumors stimulates robust anti-tumor immunity.
Tumor-infiltrating lymphocytes, particularly CD8+ cytotoxic T cells, recognize
and
attack tumor cells presenting neoantigens. However, tumors upregulate PD-L1 as
an
adaptive resistance mechanism.
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: T cell mediated cytotoxicity
modifier: INCREASED
term:
id: GO:0001913
label: T cell mediated cytotoxicity
downstream:
- target: PD-L1 Upregulation and Immune Evasion
description: Tumors adaptively upregulate checkpoint ligands to suppress T cell attack
- name: PD-L1 Upregulation and Immune Evasion
conforms_to: "immune_checkpoint_blockade#Adaptive Immune Resistance"
description: >-
MSI-H tumors upregulate PD-L1 expression in response to interferon-gamma from
infiltrating T cells. PD-L1 engagement of PD-1 on T cells suppresses cytotoxic
function,
allowing immune evasion despite the immunogenic microenvironment. This makes MSI-H
tumors vulnerable to PD-1/PD-L1 blockade.
biological_processes:
- preferred_term: Negative Regulation of T Cell Mediated Immunity
term:
id: GO:0002710
label: negative regulation of T cell mediated immunity
modifier: INCREASED
histopathology:
- name: Adenocarcinoma
finding_term:
preferred_term: Adenocarcinoma
term:
id: NCIT:C2852
label: Adenocarcinoma
frequency: VERY_FREQUENT
description: Adenocarcinoma is the most common pathologic subtype of colon cancer.
evidence:
- reference: PMID:35613396
reference_title: "[Adenosquamous carcinoma of the colon: a case report and review of the literature]."
supports: PARTIAL
snippet: "Adenocarcinoma is the most common pathologic subtype of colon cancer"
explanation: Abstract reports adenocarcinoma as the most common pathologic subtype of colon cancer.
phenotypes:
- category: Gastrointestinal
name: Colon Cancer
frequency: VERY_FREQUENT
diagnostic: true
description: >-
MSI-H colorectal cancer presents as a primary colonic malignancy, with strong
right-sided
(proximal colon) predominance. Tumors often present at earlier stage compared
to
microsatellite stable cancers.
phenotype_term:
preferred_term: Colon cancer
term:
id: HP:0003003
label: Colon cancer
- category: Gastrointestinal
name: Abdominal Pain
frequency: FREQUENT
description: >-
Abdominal discomfort or pain may result from tumor mass effect or partial obstruction,
particularly with right-sided tumors.
phenotype_term:
preferred_term: Abdominal pain
term:
id: HP:0002027
label: Abdominal pain
- category: Gastrointestinal
name: Hematochezia
frequency: FREQUENT
description: >-
Rectal bleeding may occur, though less prominent than in left-sided colorectal
cancers
due to the proximal location of most MSI-H tumors.
phenotype_term:
preferred_term: Hematochezia
term:
id: HP:0002573
label: Hematochezia
- category: Hematologic
name: Anemia
frequency: FREQUENT
description: >-
Iron deficiency anemia from chronic occult blood loss is common, particularly
with
right-sided tumors where bleeding may not produce visible hematochezia.
phenotype_term:
preferred_term: Anemia
term:
id: HP:0001903
label: Anemia
- category: Constitutional
name: Weight Loss
frequency: OCCASIONAL
description: >-
Unintentional weight loss may occur with advanced disease.
phenotype_term:
preferred_term: Weight loss
term:
id: HP:0001824
label: Weight loss
biochemical:
- name: MSI Testing
notes: >-
PCR-based testing of five microsatellite markers (Bethesda panel) or expanded
panels.
MSI-H defined as instability at two or more markers. Next-generation sequencing
can
also detect MSI status.
- name: MMR Immunohistochemistry
notes: >-
Immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 proteins. Loss of expression
indicates MMR deficiency. MLH1/PMS2 loss with concurrent BRAF V600E suggests sporadic
MSI-H; isolated MSH2/MSH6 loss suggests Lynch syndrome.
- name: Tumor Mutational Burden
notes: >-
MSI-H tumors typically have TMB greater than 10 mutations per megabase, often
20-40 mut/Mb.
High TMB correlates with checkpoint inhibitor response and can be assessed by
NGS panels.
genetic:
- name: MLH1
association: Loss of Function (Somatic or Germline)
notes: >-
MLH1 loss occurs via germline mutation (Lynch syndrome) or somatic promoter hypermethylation
(sporadic). MLH1 hypermethylation accounts for 80% of sporadic MSI-H CRC and is
often
associated with BRAF V600E mutation.
- name: MSH2
association: Germline Loss of Function
notes: >-
MSH2 germline mutations are the second most common cause of Lynch syndrome. EPCAM
deletions
can also cause MSH2 silencing through promoter methylation.
- name: MSH6
association: Germline Loss of Function
notes: >-
MSH6 germline mutations cause Lynch syndrome with attenuated phenotype and later
age of onset.
- name: PMS2
association: Germline Loss of Function
notes: >-
PMS2 germline mutations cause Lynch syndrome with lower penetrance than MLH1/MSH2
mutations.
- name: BRAF V600E
association: Somatic Activating Mutation (Sporadic MSI-H)
notes: >-
BRAF V600E is present in approximately 40-50% of sporadic MSI-H CRC, virtually
always
with MLH1 hypermethylation. Its presence excludes Lynch syndrome. Unlike MSS BRAF-mutant
CRC, MSI-H BRAF-mutant tumors respond well to checkpoint inhibitors.
treatments:
- name: Pembrolizumab
description: >-
Anti-PD-1 immune checkpoint inhibitor approved as first-line monotherapy for metastatic
MSI-H/dMMR colorectal cancer. KEYNOTE-177 demonstrated superior progression-free
survival
compared to chemotherapy with durable responses in a subset of patients.
evidence:
- reference: PMID:33264544
reference_title: "Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer."
supports: SUPPORT
snippet: "Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer"
explanation: "KEYNOTE-177 abstract reports improved progression-free survival with first-line pembrolizumab versus chemotherapy."
treatment_term:
preferred_term: immunotherapy
term:
id: NCIT:C15262
label: Immunotherapy
therapeutic_agent:
- preferred_term: pembrolizumab
term:
id: NCIT:C106432
label: Pembrolizumab
target_mechanisms:
- target: PD-L1 Upregulation and Immune Evasion
treatment_effect: INHIBITS
description: >-
Anti-PD-1 antibody blocks the PD-1/PD-L1 interaction on tumor-infiltrating
T cells, reversing adaptive immune resistance and restoring cytotoxic
T cell function against neoantigen-expressing tumor cells.
evidence:
- reference: PMID:33264544
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer"
explanation: >-
Superior PFS with anti-PD-1 monotherapy demonstrates that blocking
PD-1/PD-L1-mediated immune evasion is sufficient for tumor control
in MSI-H CRC.
- name: Nivolumab plus Ipilimumab
description: >-
Combination checkpoint blockade with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab)
approved for MSI-H/dMMR metastatic CRC. CheckMate 142 showed high response rates
and
durable disease control with combined checkpoint inhibition.
evidence:
- reference: PMID:29355075
reference_title: "Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer."
supports: SUPPORT
snippet: >-
investigator-assessed ORR was 55% (95% CI, 45.2 to 63.8), and disease control
rate for ≥ 12 weeks was 80%
explanation: >-
CheckMate-142 trial demonstrated high objective response rate (55%) and disease
control rate (80%) with nivolumab plus ipilimumab in dMMR/MSI-H mCRC.
- reference: CIVIC_EID:12561
reference_title: "MSI High / Colorectal Cancer (Predictive Sensitivity/Response)"
supports: SUPPORT
evidence_source: OTHER
snippet: nivolumab plus ipilimumab significantly improved progression-free survival versus investigator’s choice of chemotherapy
explanation: CIViC's accepted evidence item supports first-line ipilimumab/nivolumab sensitivity in MSI-high/dMMR metastatic colorectal cancer.
- reference: CIVIC_EID:12562
reference_title: "MSI High / Colorectal Cancer (Predictive Sensitivity/Response)"
supports: SUPPORT
evidence_source: OTHER
snippet: nivolumab plus ipilimumab significantly improved progression-free survival versus nivolumab monotherapy across all treatment lines
explanation: CIViC's accepted evidence item supports ipilimumab/nivolumab sensitivity across treatment lines in MSI-high/dMMR metastatic colorectal cancer.
treatment_term:
preferred_term: immunotherapy
term:
id: NCIT:C15262
label: Immunotherapy
therapeutic_agent:
- preferred_term: nivolumab
term:
id: NCIT:C68814
label: Nivolumab
- preferred_term: ipilimumab
term:
id: CHEBI:231679
label: ipilimumab
target_mechanisms:
- target: PD-L1 Upregulation and Immune Evasion
treatment_effect: INHIBITS
description: >-
Nivolumab (anti-PD-1) blocks PD-1/PD-L1-mediated T cell suppression,
while ipilimumab (anti-CTLA-4) enhances T cell priming and expands
the anti-tumor T cell repertoire.
evidence:
- reference: PMID:29355075
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
investigator-assessed ORR was 55% (95% CI, 45.2 to 63.8), and disease control
rate for ≥ 12 weeks was 80%
explanation: >-
High response rates with dual checkpoint blockade demonstrate that
combined PD-1 and CTLA-4 inhibition effectively reverses immune
evasion in MSI-H CRC.
- reference: CIVIC_EID:12561
supports: SUPPORT
evidence_source: OTHER
snippet: nivolumab plus ipilimumab significantly improved progression-free survival versus investigator’s choice of chemotherapy
explanation: CIViC's accepted evidence item supports the clinical effect of combined PD-1 and CTLA-4 blockade in MSI-high/dMMR metastatic CRC.
- name: Dostarlimab
description: >-
Anti-PD-1 antibody with remarkable activity in MSI-H rectal cancer. A single-arm
study
demonstrated 100% clinical complete response rate in locally advanced MSI-H rectal
cancer,
allowing organ preservation without surgery or radiation.
evidence:
- reference: PMID:35660797
reference_title: "PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer."
supports: PARTIAL
snippet: >-
All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete
response, with no evidence of tumor on magnetic resonance imaging,
18F-fluorodeoxyglucose-positron-emission tomography, endoscopic evaluation,
digital rectal examination, or biopsy.
explanation: >-
Phase 2 study showed 100% clinical complete response rate with dostarlimab
monotherapy in mismatch repair-deficient locally advanced rectal cancer.
treatment_term:
preferred_term: immunotherapy
term:
id: NCIT:C15262
label: Immunotherapy
therapeutic_agent:
- preferred_term: dostarlimab
term:
id: NCIT:C126799
label: Dostarlimab
target_mechanisms:
- target: PD-L1 Upregulation and Immune Evasion
treatment_effect: INHIBITS
description: >-
Anti-PD-1 antibody that blocks PD-1/PD-L1-mediated immune evasion,
enabling complete clinical responses in MSI-H rectal cancer without
surgery or radiation.
evidence:
- reference: PMID:35660797
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete
response, with no evidence of tumor on magnetic resonance imaging,
18F-fluorodeoxyglucose-positron-emission tomography, endoscopic evaluation,
digital rectal examination, or biopsy.
explanation: >-
100% complete response rate with single-agent anti-PD-1 in MSI-H
rectal cancer demonstrates the centrality of PD-1/PD-L1-mediated
immune evasion in this tumor type.
- name: Surgical Resection
description: >-
Surgery remains the primary curative treatment for localized MSI-H colorectal
cancer.
Patients with Lynch syndrome may benefit from extended colectomy due to risk of
metachronous tumors.
evidence:
- reference: PMID:35660797
reference_title: "PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer."
supports: PARTIAL
snippet: >-
Neoadjuvant chemotherapy and radiation followed by surgical resection of the
rectum is a standard treatment for locally advanced rectal cancer.
explanation: >-
The study confirms surgical resection is standard treatment for locally advanced
rectal cancer, supporting the role of surgery in MSI-H CRC.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
disease_term:
preferred_term: MSI-high colorectal cancer
term:
id: MONDO:0005575
label: colorectal cancer
mappings:
mondo_mappings:
- term:
id: MONDO:0005575
label: colorectal cancer
mapping_predicate: skos:closeMatch
mapping_source: MONDO
mapping_justification: MONDO currently provides the broader colorectal cancer anchor, but does not capture the MSI-high qualifier in the local ontology snapshot.
ncit_mappings:
- term:
id: NCIT:C2955
label: Colorectal Carcinoma
mapping_predicate: skos:closeMatch
mapping_source: NCIT
mapping_justification: NCIT provides a close morphology/site anchor for colorectal carcinoma, but not a disease term that fully captures the MSI-high qualifier.
classifications:
icdo_morphology:
classification_value: Adenocarcinoma
harrisons_chapter:
- classification_value: cancer
- classification_value: solid tumor
references:
- reference: DOI:10.1038/s41591-024-03250-w
title: 'Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial'
found_in:
- MSI_High_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: 'Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial'
supporting_text: 'Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial'
- reference: DOI:10.1093/oncolo/oyad082
title: <i>BRAF</i> V600E/<i>RAS</i> Mutations and Lynch Syndrome in Patients With MSI-H/dMMR Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors
found_in:
- MSI_High_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: <i>BRAF</i> V600E/<i>RAS</i> Mutations and Lynch Syndrome in Patients With MSI-H/dMMR Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors
supporting_text: We pooled data from 2 cohorts of immune checkpoint inhibitors-treated microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer patients to evaluate the prognostic value of RAS/BRAFV600E mutations and Lynch syndrome (LS).
evidence:
- reference: DOI:10.1093/oncolo/oyad082
reference_title: <i>BRAF</i> V600E/<i>RAS</i> Mutations and Lynch Syndrome in Patients With MSI-H/dMMR Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: We pooled data from 2 cohorts of immune checkpoint inhibitors-treated microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer patients to evaluate the prognostic value of RAS/BRAFV600E mutations and Lynch syndrome (LS).
explanation: Deep research cited this publication as relevant literature for MSI High Colorectal Cancer.
- reference: DOI:10.1159/000531003
title: 'The Day-To-Day Practice of MMR and MSI Assessment in Colorectal Adenocarcinoma: What We Know and What We Still Need to Explore'
found_in:
- MSI_High_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: The DNA mismatch repair (MMR) system is a highly preserved protein complex recognizing short insertions, short deletions, and single base mismatches during DNA replication and recombination.
supporting_text: The DNA mismatch repair (MMR) system is a highly preserved protein complex recognizing short insertions, short deletions, and single base mismatches during DNA replication and recombination.
evidence:
- reference: DOI:10.1159/000531003
reference_title: 'The Day-To-Day Practice of MMR and MSI Assessment in Colorectal Adenocarcinoma: What We Know and What We Still Need to Explore'
supports: SUPPORT
evidence_source: OTHER
snippet: The DNA mismatch repair (MMR) system is a highly preserved protein complex recognizing short insertions, short deletions, and single base mismatches during DNA replication and recombination.
explanation: Deep research cited this publication as relevant literature for MSI High Colorectal Cancer.
- reference: DOI:10.1186/s40364-024-00640-7
title: Oncological characteristics, treatments and prognostic outcomes in MMR-deficient colorectal cancer
found_in:
- MSI_High_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Colorectal cancer (CRC) ranks as the third most prevalent cancer globally.
supporting_text: Colorectal cancer (CRC) ranks as the third most prevalent cancer globally.
evidence:
- reference: DOI:10.1186/s40364-024-00640-7
reference_title: Oncological characteristics, treatments and prognostic outcomes in MMR-deficient colorectal cancer
supports: SUPPORT
evidence_source: OTHER
snippet: Colorectal cancer (CRC) ranks as the third most prevalent cancer globally.
explanation: Deep research cited this publication as relevant literature for MSI High Colorectal Cancer.
- reference: DOI:10.3389/fimmu.2022.1019582
title: 'Clinicopathological characteristics of high microsatellite instability/mismatch repair-deficient colorectal cancer: A narrative review'
found_in:
- MSI_High_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: 'Clinicopathological characteristics of high microsatellite instability/mismatch repair-deficient colorectal cancer: A narrative review'
supporting_text: Colorectal cancers (CRCs) with high microsatellite instability (MSI-H) and deficient mismatch repair (dMMR) show molecular and clinicopathological characteristics that differ from those of proficient mismatch repair/microsatellite stable CRCs.
evidence:
- reference: DOI:10.3389/fimmu.2022.1019582
reference_title: 'Clinicopathological characteristics of high microsatellite instability/mismatch repair-deficient colorectal cancer: A narrative review'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Colorectal cancers (CRCs) with high microsatellite instability (MSI-H) and deficient mismatch repair (dMMR) show molecular and clinicopathological characteristics that differ from those of proficient mismatch repair/microsatellite stable CRCs.
explanation: Deep research cited this publication as relevant literature for MSI High Colorectal Cancer.
- reference: DOI:10.3389/fonc.2023.1223915
title: Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer
found_in:
- MSI_High_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Genome integrity is essential for the survival of an organism.
supporting_text: Genome integrity is essential for the survival of an organism.
evidence:
- reference: DOI:10.3389/fonc.2023.1223915
reference_title: Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Genome integrity is essential for the survival of an organism.
explanation: Deep research cited this publication as relevant literature for MSI High Colorectal Cancer.
- reference: DOI:10.3390/cancers15174245
title: 'Immunotherapy for Colorectal Cancer with High Microsatellite Instability: The Ongoing Search for Biomarkers'
found_in:
- MSI_High_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Microsatellite instability (MSI) is a biological condition associated with inflamed tumors, high tumor mutational burden (TMB), and responses to immune checkpoint inhibitors.
supporting_text: Microsatellite instability (MSI) is a biological condition associated with inflamed tumors, high tumor mutational burden (TMB), and responses to immune checkpoint inhibitors.
evidence:
- reference: DOI:10.3390/cancers15174245
reference_title: 'Immunotherapy for Colorectal Cancer with High Microsatellite Instability: The Ongoing Search for Biomarkers'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Microsatellite instability (MSI) is a biological condition associated with inflamed tumors, high tumor mutational burden (TMB), and responses to immune checkpoint inhibitors.
explanation: Deep research cited this publication as relevant literature for MSI High Colorectal Cancer.
- reference: DOI:10.3390/diagnostics14111076
title: 'Nationwide Real-World Data of Microsatellite Instability and/or Mismatch Repair Deficiency in Cancer: Prevalence and Testing Patterns'
found_in:
- MSI_High_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Determination of microsatellite instability (MSI)/mismatch repair (MMR) status in cancer has several clinical implications.
supporting_text: Determination of microsatellite instability (MSI)/mismatch repair (MMR) status in cancer has several clinical implications.
evidence:
- reference: DOI:10.3390/diagnostics14111076
reference_title: 'Nationwide Real-World Data of Microsatellite Instability and/or Mismatch Repair Deficiency in Cancer: Prevalence and Testing Patterns'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Determination of microsatellite instability (MSI)/mismatch repair (MMR) status in cancer has several clinical implications.
explanation: Deep research cited this publication as relevant literature for MSI High Colorectal Cancer.
- reference: DOI:10.37349/etat.2024.00231
title: 'Resistance to immune checkpoint inhibitors in colorectal cancer with deficient mismatch repair/microsatellite instability: misdiagnosis, pseudoprogression and/or tumor heterogeneity?'
found_in:
- MSI_High_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Colorectal carcinoma (CRC) with deficiency of the deficient mismatch repair (dMMR) pathway/ microsatellite instability (MSI) is characterized by a high mutation load and infiltration of immune cells in the tumor microenvironment.
supporting_text: Colorectal carcinoma (CRC) with deficiency of the deficient mismatch repair (dMMR) pathway/ microsatellite instability (MSI) is characterized by a high mutation load and infiltration of immune cells in the tumor microenvironment.
evidence:
- reference: DOI:10.37349/etat.2024.00231
reference_title: 'Resistance to immune checkpoint inhibitors in colorectal cancer with deficient mismatch repair/microsatellite instability: misdiagnosis, pseudoprogression and/or tumor heterogeneity?'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Colorectal carcinoma (CRC) with deficiency of the deficient mismatch repair (dMMR) pathway/ microsatellite instability (MSI) is characterized by a high mutation load and infiltration of immune cells in the tumor microenvironment.
explanation: Deep research cited this publication as relevant literature for MSI High Colorectal Cancer.
- reference: DOI:10.5152/tjg.2024.23366
title: The Relationship Between DNA Mismatch Repair Status and Clinicopathologic Characteristics in Colon Cancer
found_in:
- MSI_High_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: DNA mismatch repair (MMR) proteins are essential for repairing genetic mutations that occur during DNA replication.
supporting_text: DNA mismatch repair (MMR) proteins are essential for repairing genetic mutations that occur during DNA replication.
evidence:
- reference: DOI:10.5152/tjg.2024.23366
reference_title: The Relationship Between DNA Mismatch Repair Status and Clinicopathologic Characteristics in Colon Cancer
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: DNA mismatch repair (MMR) proteins are essential for repairing genetic mutations that occur during DNA replication.
explanation: Deep research cited this publication as relevant literature for MSI High Colorectal Cancer.
MSI‑H CRC is a molecular subtype of colorectal adenocarcinoma characterized by microsatellite instability (MSI), which is the tumor phenotype resulting from a deficient DNA mismatch repair (dMMR) system (parente2023thedaytodaypractice pages 2-3, ros2023immunotherapyforcolorectal pages 2-4). In practical clinical terms, CRC is classified as dMMR when immunohistochemistry (IHC) shows loss of expression of ≥1 mismatch repair proteins (MLH1, MSH2, MSH6, PMS2) (parente2023thedaytodaypractice pages 2-3, normanno2024resistancetoimmune pages 1-3). MSI itself can be detected by molecular assays (PCR or NGS) as instability at microsatellite loci (ros2023immunotherapyforcolorectal pages 2-4, fan2024oncologicalcharacteristicstreatments pages 4-5).
Abstract-supported definition (verbatim): Parente et al. (2023) describe that “Deficit in one or more MMR proteins, configuring deficient MMR status (dMMR), leads to frameshift mutations particularly clustered in microsatellite repeats. Thus, microsatellite instability (MSI) is the epiphenomenon of dMMR.” (Digestive Diseases; published May 2023; https://doi.org/10.1159/000531003) (parente2023thedaytodaypractice pages 2-3).
The synthesized disease characterization in this report is derived from aggregated disease-level resources, including multi-center trials, nationwide testing datasets, reviews, and retrospective cohort studies—not single-patient EHR narratives (parente2023thedaytodaypractice pages 2-3, colle2023brafv600erasmutations pages 1-2, fan2024oncologicalcharacteristicstreatments pages 4-5, fountzilas2024nationwiderealworlddata pages 1-2).
MSI‑H CRC arises when the DNA mismatch repair system fails, due to: 1) Germline pathogenic variants in MMR genes (Lynch syndrome) (normanno2024resistancetoimmune pages 1-3, fan2024oncologicalcharacteristicstreatments pages 1-2) 2) Somatic MMR gene alterations (normanno2024resistancetoimmune pages 1-3, fan2024oncologicalcharacteristicstreatments pages 1-2) 3) Epigenetic silencing, most prominently MLH1 promoter hypermethylation, leading to loss of MLH1 (and often PMS2) protein expression (parente2023thedaytodaypractice pages 2-3, normanno2024resistancetoimmune pages 1-3, mei2022clinicopathologicalcharacteristicsof pages 6-7)
Normanno et al. (2024) explicitly state that dMMR arises from “germline/somatic mutations or epigenetic silencing (e.g., MLH1 promoter hypermethylation…)” and list core MMR proteins MSH2, MSH6, PMS2, MLH1 (published May 2024; https://doi.org/10.37349/etat.2024.00231) (normanno2024resistancetoimmune pages 1-3).
The retrieved evidence in this run does not provide primary, quantitative MSI‑H‑specific environmental or lifestyle risk modifiers beyond general CRC epidemiology. This is a gap relative to the template requirements.
Not directly supported by the retrieved evidence in this run.
Across studies and reviews, MSI‑H/dMMR CRC is associated with a characteristic “immune‑rich” histopathology: - Proximal/right‑sided colon predominance (proximal localization) (dogan2024therelationshipbetween pages 1-2) - Mucinous differentiation and other histologic patterns (medullary, signet‑ring) enriched in MSI/dMMR disease (dogan2024therelationshipbetween pages 1-2) - Tumor‑infiltrating lymphocytes (TILs) and Crohn’s‑like reaction are significantly associated with dMMR in a 200‑case series (P < .001 and P = .001, respectively) (dogan2024therelationshipbetween pages 1-2)
Abstract-supported statements (verbatim/near-verbatim): In a 200‑case CRC resection cohort, Doğan et al. (2024) report significant differences in “tumor‑infiltrating lymphocytes… Crohn’s‑like reaction… mucinous differentiation… and presence of metastatic lymph nodes” between MMR‑preserved sporadic cases and Lynch candidates (published Sep 2024; https://doi.org/10.5152/tjg.2024.23366) (dogan2024therelationshipbetween pages 1-2).
Because MSI‑H CRC is a tumor subtype, phenotype capture often maps to neoplastic and histopathologic features rather than symptoms. Suggested HPO terms include: - Colorectal carcinoma (HP:0003003; commonly used for colorectal cancer phenotyping) - Mucinous adenocarcinoma (HPO term exists for mucinous carcinoma phenotypes; confirm exact ID during curation) - Increased tumor-infiltrating lymphocytes (no single universal HPO term; may be represented via pathology annotations rather than HPO)
Note: Exact HPO identifiers for histopathology descriptors should be validated against the current HPO release; the present run did not include an HPO lookup tool.
Core genes repeatedly cited: - MLH1, MSH2, MSH6, PMS2 (parente2023thedaytodaypractice pages 2-3, normanno2024resistancetoimmune pages 1-3, fan2024oncologicalcharacteristicstreatments pages 1-2)
These correspond to proteins assessed by IHC to define dMMR in routine clinical practice (parente2023thedaytodaypractice pages 2-3, ros2023immunotherapyforcolorectal pages 2-4).
MSI‑H/dMMR CRC is described as hypermutated, yielding more neoantigens and an immune‑inflamed microenvironment with immune checkpoint upregulation, supporting response to PD‑1/PD‑L1 and CTLA‑4 blockade (parente2023thedaytodaypractice pages 2-3, normanno2024resistancetoimmune pages 1-3, ros2023immunotherapyforcolorectal pages 2-4).
Based on the mechanistic chain (dMMR → frameshift mutations → neoantigens → T‑cell infiltration → checkpoint upregulation): - GO biological processes (suggestions): DNA mismatch repair; response to DNA damage stimulus; antigen processing and presentation (MHC class I); T cell activation; interferon‑gamma signaling. - Cell Ontology (CL) suggestions: cytotoxic T cell (CD8+ T cell); T helper 1 cell; tumor-associated macrophage.
Note: Exact GO/CL IDs should be validated during curation; the run did not include ontology lookup tooling.
MSI‑H CRC is defined by tumor DNA repair biology and is most directly linked to genetic/epigenetic mechanisms. The retrieved evidence does not provide MSI‑H‑specific environmental toxicant, infectious, or lifestyle causation signals. This section should be populated from dedicated epidemiologic literature (not captured here).
1) Upstream trigger: loss of function in MMR (germline mutation, somatic mutation, or MLH1 promoter hypermethylation) (normanno2024resistancetoimmune pages 1-3, fan2024oncologicalcharacteristicstreatments pages 1-2) 2) Genomic consequence: accumulation of insertion/deletion errors at microsatellite repeats → frameshift mutations (parente2023thedaytodaypractice pages 2-3) 3) Immunogenic consequence: high tumor mutational burden and frameshift-derived neoantigens → increased immune infiltration and checkpoint expression (PD‑1/PD‑L1/CTLA‑4) (parente2023thedaytodaypractice pages 2-3, normanno2024resistancetoimmune pages 1-3, ros2023immunotherapyforcolorectal pages 2-4) 4) Therapeutic implication: strong rationale for immune checkpoint blockade; however, a subset (~30%) exhibit primary resistance to single-agent PD‑1 therapy (normanno2024resistancetoimmune pages 1-3).
Note: Exact IDs should be validated during curation.
The retrieved evidence does not provide a formal natural-history staging timeline beyond stage distribution; additional longitudinal registry studies would be needed.
Primary diagnostic modalities: - MMR IHC (MLH1/MSH2/MSH6/PMS2): loss of one or more proteins defines dMMR (parente2023thedaytodaypractice pages 2-3). - PCR-based MSI: recommended pentaplex marker sets and instability thresholds (ros2023immunotherapyforcolorectal pages 2-4). - NGS-based MSI: increasingly used; can outperform some algorithms especially in low tumor purity settings (not fully explored in retrieved evidence, but NGS use and specimen constraints are noted) (fan2024oncologicalcharacteristicstreatments pages 4-5).
Performance / discordance: - IHC and PCR concordance reported ~90–97% in CRC (ros2023immunotherapyforcolorectal pages 2-4). - Discordance reported around 1–10% in one 2024 review excerpt; under standardized conditions, a positive result from either test can be used to justify ICI use (fan2024oncologicalcharacteristicstreatments pages 4-5). - In a nationwide real‑world Greek dataset, among tumors tested by both approaches, overall discordance was 2.3% (21/904) (published May 2024; https://doi.org/10.3390/diagnostics14111076) (fountzilas2024nationwiderealworlddata pages 1-2).
A standard discriminatory concept in the retrieved sources is: - Sporadic dMMR/MSI‑H CRC: often MLH1 promoter hypermethylation, with BRAF V600E frequently present (normanno2024resistancetoimmune pages 1-3, mei2022clinicopathologicalcharacteristicsof pages 6-7). - Hereditary (Lynch) suspicion: absence of BRAF mutation and absence of MLH1 methylation raise suspicion for Lynch syndrome (mei2022clinicopathologicalcharacteristicsof pages 6-7).
In the ICI-treated metastatic cohort analysis by Colle et al. (2023), “sporadic” was operationalized as loss of MLH1/PMS2 with BRAFV600E and/or MLH1 promoter hypermethylation, or biallelic somatic MMR mutations, while Lynch required a detected germline MMR mutation (published Apr 2023; https://doi.org/10.1093/oncolo/oyad082) (colle2023brafv600erasmutations pages 1-2).
The main practical differential is false-positive/false-negative MSI/dMMR testing due to assay pitfalls or tumor heterogeneity; misdiagnosis is explicitly discussed as a contributor to apparent ICI “resistance” (normanno2024resistancetoimmune pages 1-3).
The retrieved evidence emphasizes predictive/prognostic implications rather than registry-derived survival by stage. - MSI/dMMR CRC can show resistance to 5‑FU in some contexts and strong sensitivity to immune checkpoint blockade (parente2023thedaytodaypractice pages 2-3). - A subset of metastatic MSI‑H/dMMR CRC (up to ~30%) can show progressive disease on single-agent PD‑1 therapy (normanno2024resistancetoimmune pages 1-3).
For comprehensive long-term prognosis (5‑year OS by stage), SEER/registry sources are needed and were not included in this run.
Metastatic setting - KEYNOTE‑177 (NCT02563002): Pembrolizumab as first-line therapy improved PFS vs chemotherapy. Colle et al. cite median PFS 16.5 vs 8.2 months (HR 0.60, 95% CI 0.45–0.80; P=.0002) (colle2023brafv600erasmutations pages 1-2). A 2023 review table reports ORR 43.8%, including CR 11.1% and PR 32.7%, with median PFS ~16.5 months (ros2023immunotherapyforcolorectal pages 2-4). - CheckMate‑142 (previously treated mCRC): Nivolumab monotherapy ORR 31.1% (phase II; n=74) as summarized in Normanno 2024 (normanno2024resistancetoimmune pages 1-3).
Real-world comparative effectiveness: A clinicogenomic cohort (Foundation Medicine testing across ~280 US clinics) reported in 138 MSI‑H mCRC patients that first‑line ICIs vs chemotherapy had median PFS 24.87 vs 5.65 months (AHR 0.31) and OS not reached vs 24.1 months (HR 0.45) (quintanilha2023comparativeeffectivenessof pages 1-2).
Neoadjuvant ICI for localized dMMR/MSI‑H colon cancer has shown striking pathologic regression: - NICHE‑2: MPR 95%, pCR 68% in a 2024 review excerpt (fan2024oncologicalcharacteristicstreatments pages 4-5). - NICHE‑3 (Nature Medicine 2024; NCT03026140): Nivolumab + relatlimab (anti‑PD‑1 + anti‑LAG‑3) achieved pathologic response 97% (57/59), MPR 92%, and pCR 68% (40/59), with grade 3–4 immune‑related adverse events 10% (https://doi.org/10.1038/s41591-024-03250-w) (gooyer2024neoadjuvantnivolumaband media 4e5d7e56, gooyer2024neoadjuvantnivolumaband media 37cc97ed, gooyer2024neoadjuvantnivolumaband media 1ac973b3, gooyer2024neoadjuvantnivolumaband media 592f02c3).
Note: Exact MAXO IDs should be curated separately.
The trial search retrieved multiple active studies of neoadjuvant/adjuvant PD‑1–based strategies in dMMR/MSI‑H colorectal cancer (e.g., NCT04643041 watch‑and‑wait distal rectal cancer; NCT06520683 adjuvant PD‑1 blockade high-risk stage II; NCT03926338 toripalimab ± celecoxib) (clinical trial tool output; not individually evidenced in text snippets in this run).
No MSI‑H‑specific primary prevention strategies are evidenced in the retrieved corpus beyond the implicit prevention of Lynch-associated cancers via identification and surveillance. A complete prevention section would require guideline sources (e.g., USPSTF, NCCN) not included in the tool-evidence payload.
No non-human naturally occurring MSI‑H CRC evidence was retrieved in this run.
Song et al. (Frontiers in Oncology 2023; https://doi.org/10.3389/fonc.2023.1223915) report: - Organoids derived from intestine tumors in an Msh2-deficient mouse model, with MSI‑H and high frameshift mutation frequency. - An orthotopic intra‑cecal implantation model from organoid-derived tumor fragments showing progressive growth and distant metastasis to liver and lymph node, forming adenocarcinomas “mixed with mucinous features.” The authors propose suitability for testing neoantigen-based vaccines and combination therapies (song2023organoidsandmetastatic pages 1-2).
| Topic (definition/prevalence/diagnostic criterion/trial outcome) | Key data point(s) | Source (first author, journal, year) | PMID if available (leave blank if not in evidence) | URL | Citation ID |
|---|---|---|---|---|---|
| Definition | dMMR = loss of expression of one or more MMR proteins by IHC; MSI is the molecular phenotype caused by defective mismatch repair and associated frameshift/missense mutations and neoantigen generation | Parente, Digestive Diseases, 2023 | https://doi.org/10.1159/000531003 | (parente2023thedaytodaypractice pages 2-3) | |
| Definition | Core MMR proteins implicated: MLH1, MSH2, MSH6, PMS2; dMMR can result from germline/somatic mutations or epigenetic silencing such as MLH1 promoter hypermethylation | Normanno, Exploration of Targeted Anti-tumor Therapy, 2024 | https://doi.org/10.37349/etat.2024.00231 | (normanno2024resistancetoimmune pages 1-3) | |
| Prevalence | dMMR/MSI represents ~15–20% of stage II–III CRC and ~4% of metastatic CRC | Parente, Digestive Diseases, 2023 | https://doi.org/10.1159/000531003 | (parente2023thedaytodaypractice pages 2-3) | |
| Prevalence | Stage distribution reported as ~20% in stage I–II, 13% in stage III, and 4–5% in stage IV/metastatic CRC | Normanno, Exploration of Targeted Anti-tumor Therapy, 2024 | https://doi.org/10.37349/etat.2024.00231 | (normanno2024resistancetoimmune pages 1-3) | |
| Prevalence | Alternative stage-specific summary: ~20% stage II, ~12% stage III, ~4% stage IV CRC | Fan, Biomarker Research, 2024 | https://doi.org/10.1186/s40364-024-00640-7 | (fan2024oncologicalcharacteristicstreatments pages 1-2) | |
| Hereditary vs sporadic etiology | About ~20% of dMMR/MSI CRC are Lynch syndrome-related | Parente, Digestive Diseases, 2023 | https://doi.org/10.1159/000531003 | (parente2023thedaytodaypractice pages 2-3) | |
| Hereditary vs sporadic etiology | Across all CRC, ~15% are dMMR/MSI; most are sporadic with MLH1 hypermethylation ~12%, and ~3% are due to germline MMR mutations | Normanno, Exploration of Targeted Anti-tumor Therapy, 2024 | https://doi.org/10.37349/etat.2024.00231 | (normanno2024resistancetoimmune pages 1-3) | |
| Sporadic vs Lynch discriminator | BRAF V600E co-mutation occurs in ~30% of sporadic dMMR/MSI cases | Normanno, Exploration of Targeted Anti-tumor Therapy, 2024 | https://doi.org/10.37349/etat.2024.00231 | (normanno2024resistancetoimmune pages 1-3) | |
| Diagnostic criterion | PCR pentaplex markers often used: NR-27, NR-21, NR-24, BAT-25, BAT-26; MSI-H called when ≥3/5 markers unstable (or 2 markers when paired normal tissue is used) | Ros, Cancers, 2023 | https://doi.org/10.3390/cancers15174245 | (ros2023immunotherapyforcolorectal pages 2-4) | |
| Diagnostic criterion | Alternative PCR definition reported: two or more single-nucleotide repeat fragment size changes ≥3 bp = MSI-H; one or none = non-MSI-H | Fan, Biomarker Research, 2024 | https://doi.org/10.1186/s40364-024-00640-7 | (fan2024oncologicalcharacteristicstreatments pages 4-5) | |
| Diagnostic performance | Concordance between IHC and PCR in CRC reported as 90–97% | Ros, Cancers, 2023 | https://doi.org/10.3390/cancers15174245 | (ros2023immunotherapyforcolorectal pages 2-4) | |
| Diagnostic discordance | IHC and MSI testing discordance reported at 1–10%; under standardized conditions, a positive result from either test may justify ICI use | Fan, Biomarker Research, 2024 | https://doi.org/10.1186/s40364-024-00640-7 | (fan2024oncologicalcharacteristicstreatments pages 4-5) | |
| First-line metastatic trial outcome | KEYNOTE-177: pembrolizumab vs chemotherapy, median PFS 16.5 vs 8.2 months, HR 0.60 (95% CI 0.45–0.80; P=.0002) | Colle, The Oncologist, 2023 | https://doi.org/10.1093/oncolo/oyad082 | (colle2023brafv600erasmutations pages 1-2) | |
| First-line metastatic trial outcome | KEYNOTE-177 reported ORR 43.8%, including CR 11.1% and PR 32.7%, with median PFS about 16.5 months in the PCR/IHC-defined cohort | Ros, Cancers, 2023 | https://doi.org/10.3390/cancers15174245 | (ros2023immunotherapyforcolorectal pages 2-4) | |
| Real-world implementation | In a US clinicogenomic cohort of 138 MSI-H mCRC patients receiving first-line ICIs vs chemotherapy: median PFS 24.87 vs 5.65 months (AHR 0.31), OS not reached vs 24.1 months (HR 0.45), TTNT not reached vs 7.23 months (AHR 0.17) | Quintanilha, unknown journal, 2023 | (quintanilha2023comparativeeffectivenessof pages 1-2) | ||
| Advanced disease immunotherapy outcome | CheckMate-142 nivolumab monotherapy in previously treated dMMR/MSI mCRC: ORR 31.1% (phase II; n=74) | Normanno, Exploration of Targeted Anti-tumor Therapy, 2024 | https://doi.org/10.37349/etat.2024.00231 | (normanno2024resistancetoimmune pages 1-3) | |
| Resistance estimate | Up to 30% of dMMR/MSI metastatic CRC patients may show progressive disease with single-agent anti-PD-1 therapy | Normanno, Exploration of Targeted Anti-tumor Therapy, 2024 | https://doi.org/10.37349/etat.2024.00231 | (normanno2024resistancetoimmune pages 1-3) | |
| Neoadjuvant trial outcome | NICHE-2 (ipilimumab + nivolumab): major pathologic response 95%, pathologic complete response 68% in dMMR/MSI-H colon cancer | Fan, Biomarker Research, 2024 | https://doi.org/10.1186/s40364-024-00640-7 | (fan2024oncologicalcharacteristicstreatments pages 4-5) | |
| Neoadjuvant trial outcome | NICHE-3 (nivolumab + relatlimab): 100% pathologic response, pCR 79% | Fan, Biomarker Research, 2024 | https://doi.org/10.1186/s40364-024-00640-7 | (fan2024oncologicalcharacteristicstreatments pages 4-5) | |
| Neoadjuvant trial outcome | Phase 2 NICHE-3 publication: pathologic response in 57/59 (97%), major pathologic response 54/59 (92%), pCR 40/59 (68%); grade 3–4 irAEs 10% | de Gooyer, Nature Medicine, 2024 | https://doi.org/10.1038/s41591-024-03250-w | (fan2024oncologicalcharacteristicstreatments pages 4-5) | |
| Rectal cancer organ-preservation signal | Dostarlimab neoadjuvant therapy in small stage II–III rectal cancer cohort reported clinical complete response in 12 patients with no progression/recurrence during follow-up | Parente, Digestive Diseases, 2023 | https://doi.org/10.1159/000531003 | (parente2023thedaytodaypractice pages 2-3) |
Table: This table compiles the main definitions, prevalence estimates, diagnostic thresholds, and headline immunotherapy outcomes for MSI-high/dMMR colorectal cancer from the gathered evidence. It is useful as a quick-reference summary for knowledge base population and citation tracking.
1) Neoadjuvant immunotherapy is rapidly moving from proof-of-concept toward broader clinical testing in localized dMMR colon cancer, with NICHE‑3 (2024) demonstrating very high pathologic response rates and manageable grade 3–4 irAEs at 10% (gooyer2024neoadjuvantnivolumaband media 4e5d7e56, gooyer2024neoadjuvantnivolumaband media 37cc97ed). 2) Diagnostic accuracy and correct classification (sporadic vs Lynch; true MSI/dMMR vs assay artifact) are emphasized as prerequisites for optimal immunotherapy selection, and misdiagnosis is explicitly raised as a cause of early ICI progression in MSI/dMMR mCRC (normanno2024resistancetoimmune pages 1-3). 3) Real-world data show growing MSI/MMR testing uptake and high but not perfect concordance between IHC and MSI methods (2.3% discordance in a nationwide dataset) (fountzilas2024nationwiderealworlddata pages 1-2).
These items can be filled by targeted retrieval from guideline/registry/ontology resources in a subsequent run.
References
(colle2023brafv600erasmutations pages 1-2): Raphael Colle, Sara Lonardi, Marine Cachanado, Michael J Overman, Elena Elez, Marwan Fakih, Francesca Corti, Priya Jayachandran, Magali Svrcek, Antoine Dardenne, Baptiste Cervantes, Alex Duval, Romain Cohen, Filippo Pietrantonio, and Thierry André. Braf v600e/ras mutations and lynch syndrome in patients with msi-h/dmmr metastatic colorectal cancer treated with immune checkpoint inhibitors. The Oncologist, 28:771-779, Apr 2023. URL: https://doi.org/10.1093/oncolo/oyad082, doi:10.1093/oncolo/oyad082. This article has 41 citations.
(parente2023thedaytodaypractice pages 2-3): Paola Parente, Federica Grillo, Alessandro Vanoli, Maria Cristina Macciomei, Maria Raffaella Ambrosio, Nunzia Scibetta, Emanuela Filippi, Ivana Cataldo, Luigi Baron, Giuseppe Ingravallo, Gerardo Cazzato, Laura Melocchi, Barbara Liserre, Carla Giordano, Graziana Arborea, Emanuela Pilozzi, Antonio Scapinello, Maria Costanza Aquilano, Roberta Gafà, Serena Battista, Luca Dal Santo, Michela Campora, Francesco Giuseppe Carbone, Chiara Sartori, Stefano Lazzi, Ester Hanspeter, Valentina Angerilli, Luca Mastracci, and Matteo Fassan. The day-to-day practice of mmr and msi assessment in colorectal adenocarcinoma: what we know and what we still need to explore. Digestive Diseases, 41:746-756, May 2023. URL: https://doi.org/10.1159/000531003, doi:10.1159/000531003. This article has 48 citations and is from a peer-reviewed journal.
(ros2023immunotherapyforcolorectal pages 2-4): Javier Ros, Iosune Baraibar, Nadia Saoudi, Marta Rodriguez, Francesc Salvà, Josep Tabernero, and Elena Élez. Immunotherapy for colorectal cancer with high microsatellite instability: the ongoing search for biomarkers. Cancers, 15:4245, Aug 2023. URL: https://doi.org/10.3390/cancers15174245, doi:10.3390/cancers15174245. This article has 53 citations.
(normanno2024resistancetoimmune pages 1-3): Nicola Normanno, Vincenza Caridi, Matteo Fassan, Antonio Avallone, Fortunato Ciardiello, and Carmine Pinto. Resistance to immune checkpoint inhibitors in colorectal cancer with deficient mismatch repair/microsatellite instability: misdiagnosis, pseudoprogression and/or tumor heterogeneity? Exploration of Targeted Anti-tumor Therapy, 5:495-507, May 2024. URL: https://doi.org/10.37349/etat.2024.00231, doi:10.37349/etat.2024.00231. This article has 7 citations.
(fan2024oncologicalcharacteristicstreatments pages 4-5): Wen-Xuan Fan, Fei Su, Yan Zhang, Xiao-Ling Zhang, Yun-Yi Du, Yang-Jun Gao, Wei-Ling Li, Wen-Qing Hu, and Jun Zhao. Oncological characteristics, treatments and prognostic outcomes in mmr-deficient colorectal cancer. Biomarker Research, Aug 2024. URL: https://doi.org/10.1186/s40364-024-00640-7, doi:10.1186/s40364-024-00640-7. This article has 27 citations and is from a peer-reviewed journal.
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