PMS2

Overview

PMS2 (PMS1 Homolog 2, Mismatch Repair System Component) is one of the four canonical mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2). Germline loss-of-function mutations cause Lynch syndrome with heightened risk of colorectal, endometrial, and other cancers. Somatic PMS2 mutations contribute to dMMR/MSI-H tumors and predict response to immune checkpoint blockade.

Alterations observed in the corpus

  • PMS2 somatic and germline mutations detected in dMMR/MSI-H gynecologic cancers (endometrial, ovarian); 30% of the nivolumab trial cohort harbored pathogenic somatic MMR gene mutations spanning MSH2, MSH6, MLH1, and PMS2 PMID:38653864.
  • PMS2 deleterious MMR gene alterations identified in 75% of MSI-H/dMMR prostate cancer patients; PMS2 mutations were absent (0%) in the TMB-H/MSS prostate cancer subgroup, confirming specificity for the MSI-H phenotype PMID:38949888.
  • PMS2 loss identified in 36/842 (4%) MMR-D tumors in the MiMSI pan-cancer MSK-IMPACT cohort; intermediate genomic features with TMB not significantly different from MSH6 loss (P=0.62) or MLH1 loss (P=0.96). PMID:39746944
  • Lynch syndrome (germline MMR gene mutation, including PMS2) identified in 17/2,637 (0.7%) PDAC patients; 6/17 were MSI-H; PMS2 is one of the four MMR genes contributing to this Lynch-PDAC subset. PMID:39753968
  • Hypermutator Phenotype: In glioblastoma, compromised mismatch repair (including PMS2) is identified as a prerequisite for the development of a hypermutator phenotype upon tumor recurrence after treatment with temozolomide PMID:18772890.
  • Mismatch-repair gene mutated in hypermutated colorectal tumors in the 276-tumor TCGA CRC cohort PMID:22810696
  • Somatic mutation identified in pancreatic acinar cell carcinomas but not correlated with elevated mutation burden; distinct from the MSH2-biallelic MSI-H case (ACINAR01) in this cohort PMID:24293293
  • Germline loss-of-function confers Lynch syndrome gastric cancer risk; included in standard multigene GC panel alongside MLH1, MSH2, MSH6, and EPCAM PMID:24816255
  • In PAAD, PMS2 was 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
  • Germline Lynch-syndrome gene mutated in half of MSI periampullary tumor patients — a marked enrichment vs. <5% population frequency PMID:26804919
  • Homozygous S459X germline variant diagnostic of constitutional mismatch-repair deficiency (CMMRD) syndrome in a pediatric patient with T-cell lymphoblastic lymphoma and consanguineous parentage PMID:28007021
  • MSH2, MLH1, MSH6, and PMS2 are altered in 3% of advanced prostate cancers; MMR-gene alterations produce a hypermutator phenotype with MMR/MSI signatures, raising potential for immune-checkpoint blockade response PMID:28825054
  • Assessed by IHC for MMR status alongside MLH1, MSH2, MSH6 in 1,640 mCRC tumors; IHC concordance with MSIsensor was 98.6% PMID:29316426

Cancer types (linked)

  • Endometrial cancer (UCEC) / ovarian cancer (OVT) — PMS2 mutations contribute to dMMR defining nivolumab eligibility and response PMID:38653864.
  • Prostate cancer (PRAD) — PMS2 mutations exclusively in MSI-H/dMMR subgroup; absent in TMB-H/MSS prostate cancer PMID:38949888.
  • Pan-cancer (MSK-IMPACT cohort) — PMS2 loss in 4% of MMR-D tumors across all cancer types; TMB intermediate between MLH1- and MSH6-loss cases. PMID:39746944
  • Pancreatic adenocarcinoma (PAAD) — PMS2 implicated in Lynch syndrome subset (0.7% of PDAC) with 35% MSI-H rate. PMID:39753968
  • Glioblastoma (GB) — Mismatch repair deficiency involving PMS2 facilitates the emergence of a hypermutator phenotype following alkylating agent treatment (temozolomide) PMID:18772890.

Co-occurrence and mutual exclusivity

  • Co-occurs with MLH1, MSH2, and MSH6 mutations in defining the dMMR phenotype across gynecologic and prostate cancers PMID:38653864 PMID:38949888.
  • PMS2 mutations are specifically enriched in MSI-H/dMMR prostate cancer vs. TMB-H/MSS (0% vs. 75%), underscoring its specificity for the MMR-deficient molecular class PMID:38949888.

Therapeutic relevance

  • dMMR status (including PMS2 loss) predicts response to PD-1 blockade (nivolumab) in gynecologic cancers; ORR 58.8% in this cohort PMID:38653864.
  • MSI-H/dMMR prostate cancer (PMS2-mutant inclusive) can achieve profound, durable responses to immune checkpoint blockade PMID:38949888.

Open questions

  • Whether the mechanism of dMMR (germline vs. somatic PMS2 loss vs. MLH1 hypermethylation) differentially predicts immunotherapy response remains under investigation; no significant difference was observed by dMMR mechanism in the nivolumab gynecologic cancer trial PMID:38653864.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:22810696

This page was processed by crosslinker on 2026-05-14. - PMID:24293293

This page was processed by crosslinker on 2026-05-14. - PMID:24816255

This page was processed by crosslinker on 2026-05-14. - PMID:25855536

This page was processed by crosslinker on 2026-05-14. - PMID:26804919

This page was processed by wiki-cli on 2026-05-14. - PMID:28007021

This page was processed by wiki-cli on 2026-05-14. - PMID:28825054

This page was processed by entity-page-writer on 2026-05-15. - PMID:29316426

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