MSH2

Overview

MSH2 is a core component of the mismatch repair complex (MutSalpha with MSH6; MutSbeta with MSH3). Germline mutations in MSH2 cause Lynch syndrome, predisposing to colorectal, endometrial, and other cancers. Somatic MSH2 inactivation produces MSI-H tumors sensitive to immune checkpoint blockade.

Alterations observed in the corpus

  • Somatic and germline MSH2 mutations detected in dMMR/MSI-H gynecologic cancers; 30% of cases harbored pathogenic somatic MMR gene mutations including MSH2 PMID:38653864
  • In glioblastoma treated with temozolomide, alterations in mismatch repair genes including MSH2 are associated with a hypermutator phenotype when MGMT is methylated PMID:18772890.
  • MSH2 mutations with loss of protein expression by IHC in treatment-refractory corticotroph pituitary neuroendocrine tumors PMID:38758238
  • Deleterious MSH2 alterations in 75% of MSI-H/dMMR prostate cancers; MSH2 altered in 6% of TMB-H/MSS tumors (P<0.001 difference) PMID:38949888
  • MSH2 protein loss detected in 166/842 (20%) MMR-D tumors in a prospective pan-cancer cohort; significantly higher TMB than MLH1-loss tumors (median 46.5 vs 37.7 mut/Mb, P=0.0013). One discordant MSI-H false-positive case (Sample_54409, colon adenocarcinoma) carried an MSH2 E580* nonsense variant alongside a dominant POLE exonuclease-domain signature. 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
  • Mismatch-repair gene mutated in hypermutated colorectal tumors in the 276-tumor TCGA CRC cohort PMID:22810696
  • Biallelic somatic mutation in ACINAR01 (MSI-H pancreatic acinar cell carcinoma), with >90% of sequenced tags mutated; clear causal driver of microsatellite instability in this tumor PMID:24293293
  • Germline loss-of-function confers Lynch syndrome gastric cancer risk; standard multigene panel for familial gastric cancer includes MSH2 alongside MLH1, MSH6, PMS2, and EPCAM PMID:24816255
  • MSH2 deleterious mutation identified in one of the three NSCLC patients with the highest mutation burden who achieved durable clinical benefit on pembrolizumab, consistent with mismatch-repair-driven hypermutation; MSH2 loss identified as a DNA repair mechanism elevating TMB and PD-1 response. PMID:25765070
  • In pancreatic ductal adenocarcinoma (PAAD), MSH2 loss was identified among mismatch-repair gene alterations in the top mutation-burden quartile; affected cases displayed T→C-at-CTG signatures consistent with MMR deficiency. PMID:25855536
  • In metastatic castration-resistant prostate cancer (mCRPC), MSH2 alterations were among MMR gene changes in 3 of 4 hypermutated (~50 mutations/Mb) cases. PMID:26000489
  • MSH2 mutations, together with MSH6 and MLH1, account for MMR deficiency in 12% of ATC vs 2% of PDTC; associated with hypermutator phenotype in anaplastic thyroid carcinoma PMID:26878173
  • MSH2, together with MSH6, underlies complex structural aberrations causing hypermutation in 5 men with metastatic castration-resistant prostate cancer (mCRPC); MMR deficiency apparent in matched primaries PMID:26928463
  • Mismatch repair defect identified in hypermutated HNSC tumors, alongside MLH1, MSH6, and POLD1 PMID:27442865
  • R680 missense mutation in 1/19 sequenced 1p/19q-codeleted oligodendroglioma cases PMID:28472509
  • MMR gene altered in ~3% of advanced prostate cancer patients alongside MLH1, MSH6, and PMS2; alterations produce a hypermutator phenotype with MMR/MSI signatures suggesting immune-checkpoint blockade candidacy PMID:28825054
  • Low MSH2 expression was identified in one of the two sarcoma tumors (along with an MSH6 frameshift mutation in the other) with the COSMIC6 mismatch repair signature and highest mutational burden 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
  • One pLoF likely pathogenic/pathogenic variant in German pediatric cancer predisposition cohort (n=390); reached significance in joint analysis with Zhang et al. (OR=7.1, p=.039); MSH2 is the only DNA-repair gene consistently associated with childhood cancer in a prior meta-analysis. PMID:29489754

Cancer types (linked)

  • Gynecologic cancers: MSH2 somatic/germline mutations contribute to dMMR; nivolumab achieves durable responses in MSH2-deficient tumors PMID:38653864
  • Glioblastoma (GB) — MSH2 is part of the mismatch repair pathway whose compromise, in the presence of MGMT methylation and temozolomide treatment, leads to hypermutation PMID:18772890.
  • Prostate cancer: MSH2 alterations enriched in MSI-H/dMMR subset; associated with ICB response PMID:38949888
  • Pituitary neuroendocrine tumors: MSH2 mutations in aggressive, treatment-refractory corticotroph PitNETs PMID:38758238

Co-occurrence and mutual exclusivity

Therapeutic relevance

Open questions

  • The relative contributions of individual MMR gene defects (MSH2 vs. MLH1 vs. MSH6) to differential ICB outcomes within dMMR populations are not well characterized.

Sources

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