MLH1

Overview

MLH1 is a key mismatch repair (MMR) gene whose inactivation — via somatic mutation, germline mutation, or promoter hypermethylation — produces microsatellite instability-high (MSI-H) tumors with high neoantigen burden and sensitivity to immune checkpoint blockade. MLH1 loss is the most common MMR defect in sporadic endometrial and colorectal cancers, typically through promoter hypermethylation.

Alterations observed in the corpus

  • Promoter hypermethylation in 66% of dMMR/MSI-H gynecologic cancer cohort (n=35) treated with nivolumab; mechanism of dMMR (epigenetic vs. genetic) was not associated with differential response PMID:38653864
  • In glioblastoma treated with temozolomide, alterations in mismatch repair genes including MLH1 are associated with a hypermutator phenotype when MGMT is methylated PMID:18772890.
  • Somatic mutations and protein expression loss by IHC detected in a subset of treatment-refractory corticotroph pituitary neuroendocrine tumors (PitNETs); 5 refractory corticotroph tumors had MMR gene mutations confirmed by IHC PMID:38758238
  • Truncating mutation identified in one non-GNH hypermutator diffuse pleural mesothelioma case (MSI-high) PMID:38630790
  • Deleterious MMR gene alterations (MLH1, MSH2, MSH6, PMS2) in 75% of MSI-H/dMMR prostate cancers; MLH1 altered in 3% of TMB-H/MSS prostate cancers PMID:38949888
  • MLH1 protein loss detected in 580/842 (69%) MMR-D tumors in a prospective pan-cancer cohort (MiMSI study); associated with the highest indel/SNV ratio (median 0.57) and highest MMR-signature contribution (median 0.67) among the four MMR proteins. 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
  • Germline P/LP variant identified as incidental finding in GIST; tumor was microsatellite-stable suggesting germline variant was not a driver PMID:36593350
  • Epigenetically silenced via promoter methylation in 19 of 23 MSI-H hypermutated colorectal tumors (276-tumor TCGA CRC cohort) PMID:22810696
  • Nonsense mutation plus deletion in one neuroblastoma patient (Broad, 240 tumors); associated with hyper-mutated phenotype PMID:23334666
  • Promoter hypermethylation drives MSI/CIMP (MC1) phenotype in the MSI hypermutated subgroup (~28%) of 373 endometrial carcinomas; MLH1 mRNA expression decreased in MSI tumors PMID:23636398
  • Promoter methylation detected in 1/23 pancreatic acinar cell carcinomas by qMSP (ACINAR06) and equivocal in ACINAR18; did not correlate with MSI status PMID:24293293
  • Homozygous loss-of-function in PanNET patient PN4 (together with MSH6); 18% microsatellite instability but predicted MSI-low, illustrating that dMMR does not equal MSI-high in non-colorectal neuroendocrine neoplasms PMID:24326773
  • Germline loss-of-function confers Lynch syndrome gastric cancer risk; somatic MLH1 promoter hypermethylation underlies many MSI-high familial intestinal gastric tumors; included in standard multigene GC panel PMID:24816255
  • MLH1 promoter hypermethylation drives the MSI subtype (gastric-CIMP) in gastric cancer (EGC) PMID:25079317
  • Frameshift mutation (MM20T) driving hypermutator phenotype in uterine/ovarian carcinosarcoma; MMR-deficient cases flagged as candidates for anti-PD-1 immunotherapy PMID:25233892
  • MLH1 not specifically highlighted but MLH1/MLH3 are part of MMR/mismatch-repair pathway alterations in PDA (109-case WES cohort) PMID:25855536
  • MLH1 MMR alteration in 3 of 4 hypermutated mCRPC cases (~50 mutations/Mb) in the SU2C–PCF 150-case prospective WES cohort; MMR deficiency in ~2% of cases PMID:26000489
  • MLH1 mutations, together with MSH2 and MSH6, account for MMR deficiency in 12% of ATC vs 2% of PDTC; associated with hypermutator phenotype in anaplastic thyroid carcinoma PMID:26878173
  • MLH1 somatic alterations observed in pan-lung cancer TCGA analysis (n=1144) across lung adenocarcinoma and squamous cell carcinoma subtypes PMID:27158780
  • Mismatch repair defect identified in hypermutated HNSC tumors, alongside MSH2, MSH6, and POLD1 PMID:27442865
  • DNA-repair PPGM gene enriched in 500-patient MET500 metastatic cancer cohort vs. ExAC controls PMID:28783718
  • MMR gene altered in ~3% of advanced prostate cancer patients; alterations produce a hypermutator phenotype with MMR/MSI signatures, raising potential for immune-checkpoint blockade response PMID:28825054
  • Somatic MLH1 mutation identified as the driver of one of two cohort hypermutators (ICGC_MB265) in 491-sample medulloblastoma genome-wide analysis PMID:28726821
  • 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)

  • Gynecologic cancers (endometrial, ovarian): MLH1 promoter hypermethylation is the dominant mechanism of MMR deficiency, accounting for 66% of dMMR cases in a nivolumab phase 2 trial PMID:38653864
  • Glioblastoma (GB) — MLH1 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: deleterious MLH1 alterations enriched in MSI-H/dMMR subset (2.8% of 2,251 patients); rare in TMB-H/MSS tumors PMID:38949888
  • Pituitary neuroendocrine tumors: MLH1 mutations with protein loss in aggressive, treatment-refractory corticotroph PitNETs PMID:38758238
  • Diffuse pleural mesothelioma: rare hypermutator phenotype associated with MLH1 truncating mutation PMID:38630790

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • dMMR/MSI-H status conferred by MLH1 loss predicts response to nivolumab (anti-PD-1) in gynecologic cancers; durable responses observed regardless of whether dMMR was genetic or epigenetic in origin PMID:38653864
  • MLH1-deficient treatment-refractory PitNETs may respond to pembrolizumab; dramatic responses reported in this context PMID:38758238
  • MSI-H/dMMR prostate cancer responds to immune checkpoint blockade; MLH1 alterations identify patients most likely to respond PMID:38949888

Open questions

  • Whether epigenetic (hypermethylation-driven) vs. genetic MLH1 loss predicts differential response to specific PD-1 inhibitors remains debated across studies PMID:38653864

Sources

This page was processed by entity-page-writer on 2026-05-15. - PMID:36593350

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:23334666

This page was processed by entity-page-writer on 2026-05-15. - PMID:23636398

This page was processed by entity-page-writer on 2026-05-15. - PMID:24293293

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:24816255

This page was processed by entity-page-writer on 2026-05-15. - PMID:25079317

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: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:27158780

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:28783718

This page was processed by wiki-cli on 2026-05-15. - PMID:28825054

This page was processed by wiki-cli on 2026-05-15. - PMID:28726821

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

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