MSH6

Overview

MSH6 forms the MutSalpha heterodimer with MSH2 to recognize single-base mismatches and short insertions/deletions. Germline MSH6 mutations cause Lynch syndrome. In gliomas, MSH6 somatic mutations emerge under alkylating chemotherapy pressure and produce a hypermutation phenotype at recurrence. In MSI-H tumors of other types, MSH6 loss confers sensitivity to immune checkpoint blockade.

Alterations observed in the corpus

  • Somatic MSH6 mutations in recurrent IDH-mutant gliomas linked to hypermutation phenotype after alkylator (temozolomide) chemotherapy; treatment-induced epigenetic evolution toward aggressive phenotype PMID:38117484
  • In glioblastoma treated with temozolomide, MSH6 mutations combined with MGMT promoter methylation are associated with a hypermutator phenotype PMID:18772890.
  • Somatic and germline MSH6 mutations in dMMR/MSI-H gynecologic cancers; 30% of cases harbored pathogenic somatic MMR gene mutations including MSH6 PMID:38653864
  • MSH6 mutations with protein loss by IHC in treatment-refractory corticotroph pituitary neuroendocrine tumors PMID:38758238
  • Deleterious MSH6 alterations in 75% of MSI-H/dMMR prostate cancers; MSH6 altered in 9% of TMB-H/MSS tumors PMID:38949888
  • MSH6 protein loss detected in 60/842 (7%) MMR-D tumors in a prospective pan-cancer cohort; lowest indel/SNV ratio (median 0.09) and lowest MMR-signature contribution (median 0.42) among the four MMR proteins. TMB not significantly different from PMS2-loss (P=0.62) or MLH1-loss (P=0.96). PMID:39746944
  • MMR gene alterations (MLH1, MSH2, MSH6, PMS2) identified as Lynch syndrome in 17/2,336 PDAC patients (0.7%); 6/17 were MSI-H. PMID:39753968
  • MSH6 alterations were identified among recurrent genomic changes in prostate cancer by integrative genomic profiling of the MSKCC cohort PMID:20579941
  • MSH6 somatic mutations identified in prostate cancer by WES of 112 primary tumors (Broad Institute cohort), implicating mismatch repair deficiency PMID:22610119
  • Mismatch-repair gene mutated in hypermutated colorectal tumors in the 276-tumor TCGA CRC cohort PMID:22810696
  • Co-mutated with MSH3 in the most hypermutated MSI-positive esophageal adenocarcinoma case (mutation frequency 14.6–50.9/Mb) in the 149-tumor Broad WES cohort; this MSI-positive case was excluded from the main significance analysis PMID:23525077
  • Homozygous loss-of-function in PanNET patient PN4 (together with MLH1); TMB ~11 mut/Mb but predicted MSI-low, illustrating that dMMR does not equal MSI-high in non-colorectal neuroendocrine neoplasms PMID:24326773
  • Somatic MMR gene mutations (including MSH6) acquired in hypermutated low-grade glioma recurrences post-temozolomide; loss of MSH6 and other MMR components enables continued TMZ-induced hypermutation via microsatellite instability PMID:24336570
  • Germline loss-of-function confers Lynch syndrome gastric cancer risk; standard multigene panel for familial gastric cancer includes MSH6 alongside MLH1, MSH2, PMS2, and EPCAM PMID:24816255
  • Nonsense/frameshift mutations in 3 of 22 uterine/ovarian carcinosarcoma cases (MM04T, MM12T biallelic, MM18T); driver of mutator phenotype; MMR-deficient tumors nominated as candidates for anti-PD-1 immunotherapy (pembrolizumab) PMID:25233892
  • MSH6 mismatch-repair defect detected in hypermutated gastric adenocarcinoma (Pt1); co-occurs with TGFBR2, KDM5A, and KMT2D in the hypermutated subclone PMID:25583476
  • In pancreatic ductal adenocarcinoma (PAAD), MSH6 loss was identified among mismatch-repair gene alterations in the top mutation-burden quartile; affected cases displayed MMR deficiency signatures. PMID:25855536
  • In mCRPC, MSH6 was among MMR gene alterations in hypermutated cases; MMR deficiency contributing to ~50 mutations/Mb. PMID:26000489
  • MSH6 mutations, together with MSH2 and MLH1, account for MMR deficiency in 12% of ATC vs 2% of PDTC; associated with hypermutator phenotype in anaplastic thyroid carcinoma PMID:26878173
  • MSH6, together with MSH2, underlies complex structural aberrations causing hypermutation in 5 men with mCRPC; MMR deficiency apparent in matched primaries, supporting MMR-deficiency testing in metastatic prostate cancer PMID:26928463
  • Mismatch repair defect identified in hypermutated HNSC tumors, alongside MLH1, MSH2, and POLD1 PMID:27442865
  • Somatic mutation observed in the hypermutated clear-cell endometrial carcinoma (CCEC) case T113; associated with MSI-high tumor phenotype PMID:28485815
  • Less frequent DDR alteration in non-muscle-invasive bladder cancer (NMIBC); contributes to the 30% DDR-altered fraction seen in high-grade NMIBC PMID:28583311
  • MMR gene altered in ~3% of advanced prostate cancer patients alongside MLH1, MSH2, and PMS2; alterations produce a hypermutator phenotype with MMR/MSI signatures suggesting immune-checkpoint blockade candidacy PMID:28825054
  • A frameshift mutation in MSH6 was found in one of two sarcomas with the highest mutational burden and COSMIC6 mismatch repair signature in the TCGA sarcoma cohort PMID:29100075
  • Assayed by IHC for MMR protein status in mCRC (N=1,152); concordance between IHC-based MMR status and MSIsensor score was 98.6% PMID:29316426

Cancer types (linked)

  • Glioma (IDH-mutant): MSH6 mutations are a key resistance mechanism to temozolomide, producing hypermutated recurrent tumors PMID:38117484
  • Glioblastoma (GB) — Somatic MSH6 mutations identified in the context of alkylating agent treatment and MGMT methylation, leading to hypermutation PMID:18772890.
  • Gynecologic cancers: MSH6 mutations contribute to dMMR; nivolumab achieves durable responses in MSH6-deficient tumors PMID:38653864
  • Prostate cancer: MSH6 alterations enriched in MSI-H/dMMR subset; associated with ICB response PMID:38949888
  • Pituitary neuroendocrine tumors: MSH6 mutations in aggressive, treatment-refractory corticotroph PitNETs PMID:38758238

Co-occurrence and mutual exclusivity

Therapeutic relevance

Open questions

  • Whether hypermutated gliomas with treatment-induced MSH6 mutations respond to immune checkpoint blockade has not been prospectively evaluated.

Sources

This page was processed by entity-page-writer on 2026-05-15. - PMID:20579941

This page was processed by entity-page-writer on 2026-05-15. - PMID:22610119

This page was processed by entity-page-writer on 2026-05-15. - PMID:22810696

This page was processed by entity-page-writer on 2026-05-15. - PMID:23525077

This page was processed by entity-page-writer on 2026-05-15. - PMID:24326773

This page was processed by entity-page-writer on 2026-05-15. - PMID:24336570

This page was processed by entity-page-writer on 2026-05-15. - PMID:24816255

This page was processed by entity-page-writer on 2026-05-15. - PMID:25233892

This page was processed by entity-page-writer on 2026-05-15. - PMID:25583476

This page was processed by entity-page-writer on 2026-05-15. - PMID:25855536

This page was processed by entity-page-writer on 2026-05-15. - PMID:26000489

This page was processed by entity-page-writer on 2026-05-15. - PMID:26878173

This page was processed by entity-page-writer on 2026-05-15. - PMID:26928463

This page was processed by entity-page-writer on 2026-05-15. - PMID:27442865

This page was processed by entity-page-writer on 2026-05-15. - PMID:28485815

This page was processed by entity-page-writer on 2026-05-15. - PMID:28583311

This page was processed by entity-page-writer on 2026-05-15. - PMID:28825054

This page was processed by wiki-cli on 2026-05-15. - PMID:29100075

This page was processed by wiki-cli on 2026-05-15. - PMID:29316426

This page was processed by wiki-cli on 2026-05-15.