MSH3

Overview

MSH3 forms the MutSbeta heterodimer with MSH2 to recognize insertion-deletion loops during DNA mismatch repair. Biallelic MSH3 inactivation causes a microsatellite instability phenotype at dinucleotide repeats. MSH3 mutations are observed as co-mutations in BRAF fusion-positive colorectal cancer and in MSI-H prostate cancer.

Alterations observed in the corpus

  • Frequent co-mutation in BRAF fusion-positive colorectal cancers (along with RNF43, KMT2D, and ARID1A); identified in a tumor-agnostic cohort of 833 patients across 52 histologies PMID:38922339.
  • Identified as a shared putative oncogenic mutation in an exceptional responder case of MSI-H/dMMR prostate cancer; clonal relatedness confirmed across serial tumor samples PMID:38949888.
  • Mismatch-repair gene mutated in hypermutated colorectal tumors in the 276-tumor TCGA CRC cohort PMID:22810696
  • Co-mutated with MSH6 in the most hypermutated MSI-positive esophageal adenocarcinoma (EAC) case in the 149-tumor Broad WES cohort; this MSI-positive case was excluded from significance analysis PMID:23525077
  • Somatic mutation in ACINAR01 (MSI-H) and other pancreatic acinar cell carcinomas; pathogenic significance unclear PMID:24293293
  • Heterozygous variant of uncertain significance (VUS) in PanNET patient PN1; MSI-stable prediction by MSIsensor PMID:24326773

Cancer types (linked)

  • Colorectal cancer (BRAF fusion-positive) — frequent co-mutation; may contribute to the MMR-deficient phenotype observed in some BRAF fusion-driven CRCs PMID:38922339.
  • Prostate cancer (MSI-H/dMMR) — clonal MSH3 mutation in an exceptional ICB responder PMID:38949888.

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • MSH3 co-mutation in BRAF fusion-positive CRC may indicate MMR deficiency and thus potential sensitivity to immune checkpoint blockade.
  • Clonal MSH3 mutation in MSI-H prostate cancer associated with durable ICB response PMID:38949888.

Open questions

  • Whether MSH3 mutations in BRAF fusion-positive CRC are a cause or consequence of the MMR-deficient phenotype is not resolved.

Sources

This page was processed by crosslinker on 2026-05-09. - PMID:22810696

This page was processed by crosslinker on 2026-05-09. - PMID:23525077

This page was processed by crosslinker on 2026-05-09. - PMID:24293293

This page was processed by crosslinker on 2026-05-09. - PMID:24326773

This page was processed by crosslinker on 2026-05-09.