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    GENE:

    MLH1 (MutL homolog 1)

    i
    Other names: MLH1, COCA2, FCC2, HNPCC, HNPCC2, MutL homolog 1
    1d
    Mismatch repair deficiency and microsatellite instability in adrenocortical carcinoma. (PubMed, ESMO Open)
    DMMR occurs in a minority of ACC, often without MSI. Although Lynch syndrome accounts for a subset of cases, dMMR is not predictive of clinical features or ICI response. Nonetheless, MMR testing remains important for identifying individuals at hereditary cancer risk.
    Journal • Mismatch repair • Microsatellite instability • IO biomarker
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    MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2)
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    MSI-H/dMMR
    1d
    LEAH: Cohort Evaluation of Body Fluids Early Detection of Cancer in High-risk Individuals (clinicaltrials.gov)
    P=N/A, N=5909, Not yet recruiting, Gustave Roussy, Cancer Campus, Grand Paris | Initiation date: Jun 2025 --> Feb 2026
    Trial initiation date
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    TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • STK11 (Serine/threonine kinase 11) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • POLE (DNA Polymerase Epsilon) • RUNX1 (RUNX Family Transcription Factor 1) • BAP1 (BRCA1 Associated Protein 1) • ETV6 (ETS Variant Transcription Factor 6) • MLH1 (MutL homolog 1) • CDK4 (Cyclin-dependent kinase 4) • MSH2 (MutS Homolog 2) • SMAD4 (SMAD family member 4) • CDH1 (Cadherin 1) • SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) • POLD1 (DNA Polymerase Delta 1) • RAD51C (RAD51 paralog C) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • RAD51D (RAD51 paralog D) • DDX41 (DEAD-Box Helicase 41) • GATA2 (GATA Binding Protein 2) • DICER1 (Dicer 1 Ribonuclease III) • FLCN (Folliculin) • PRSS1 (Serine Protease 1) • SDHD (Succinate Dehydrogenase Complex Subunit D) • TXNIP (Thioredoxin Interacting Protein) • ANKRD26 (Ankyrin Repeat Domain Containing 26) • BMPR1A (Bone Morphogenetic Protein Receptor Type 1A) • HOXB13 (Homeobox B13)
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    TP53 mutation • PTEN deletion
    2d
    Metagenomic Evaluation of the Gut Microbiome in Patients With Lynch Syndrome and Other Hereditary Colonic Polyposis Syndromes (clinicaltrials.gov)
    P=N/A, N=77, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Feb 2026 --> Feb 2027 | Trial primary completion date: Feb 2026 --> Feb 2027
    Trial completion date • Trial primary completion date
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    STK11 (Serine/threonine kinase 11) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • SMAD4 (SMAD family member 4) • APC (APC Regulator Of WNT Signaling Pathway) • EPCAM (Epithelial cell adhesion molecule) • BMPR1A (Bone Morphogenetic Protein Receptor Type 1A)
    2d
    Complete remission induced by immunotherapy in peritoneal carcinomatosis due to colorectal cancer (PubMed, Medicina (B Aires))
    She started combination therapy with ipilimumab and nivolumab, achieving complete metabolic and imaging response as confirmed by PET-CT at 12 months...She started treatment with pembrolizumab, achieving a sustained complete response at 12 months...Both cases illustrate the remarkable clinical benefit of immunotherapy in patients with early peritoneal recurrence of MSI-H/dMMR colon cancer, which is usually associated with poor prognosis. These cases highlight the need to consider the molecular profile in therapeutic planning and reinforce the emerging value of immunotherapy as a cornerstone in the management of these cases.
    Journal • MSi-H Biomarker • PD(L)-1 Biomarker • IO biomarker
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    MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • PMS2 (PMS1 protein homolog 2)
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    MSI-H/dMMR
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    Keytruda (pembrolizumab) • Opdivo (nivolumab) • Yervoy (ipilimumab)
    3d
    Exploring Microsatellite Instability in Endometrial Carcinomas: Clinicopathological Correlations and Clinical Implications-A Study from North India. (PubMed, Indian J Surg Oncol)
    MSI testing which has been used historically to identify patients with Lynch Syndrome and evaluate the severity and prognosis of MSI carcinomas now plays an important role in identifying patients who will benefit from targetable therapy. MMR study therefore recommended in all cases of endometrial carcinomas and detection of MMR proteins by IHC can indirectly reflect the status of MSI and is a reliable method of MSI detection.
    Journal • Microsatellite instability • IO biomarker
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    MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2)
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    MSI-H/dMMR
    4d
    Radiation and TSR-042 (Dostarlimab) in People With Endometrial Cancer After They Receive Surgery (clinicaltrials.gov)
    P2, N=62, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Feb 2026 --> Feb 2027 | Trial primary completion date: Feb 2026 --> Feb 2027
    Trial completion date • Trial primary completion date • Checkpoint inhibition • Mismatch repair • MSI-H • dMMR
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    MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2)
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    MSI-H/dMMR • POLE mutation
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    Jemperli (dostarlimab-gxly)
    5d
    Neoadjuvant mFOLFOX6 Chemotherapy Combined With Anti-PD-1 Therapy in MSS/pMMR Locally Advanced Rectal Cancer (FIRM02 Study) (clinicaltrials.gov)
    P2, N=128, Not yet recruiting, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
    New P2 trial • pMMR
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    MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2)
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    5-fluorouracil • oxaliplatin • leucovorin calcium • Hetronifly (serplulimab)
    5d
    Increased immunogenicity of hypermutated SB28 syngeneic glioblastoma is partially mediated by alterations in tumor chemokine expression. (PubMed, Neurooncol Adv)
    Clones were injected subcutaneously or intracranially with or without anti-PD-1/anti-CTLA4 and dexamethasone...Rather, rejection depended on increased secretion of pro-inflammatory chemokines. Msh2 and Mlh1 loss was not equivalent, suggesting that additional studies are needed to elucidate germline and somatic mismatch repair gene-specific immune alterations.
    Journal • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker
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    TMB (Tumor Mutational Burden) • IFNG (Interferon, gamma) • MLH1 (MutL homolog 1) • MSH2 (MutS Homolog 2) • CXCL10 (Chemokine (C-X-C motif) ligand 10) • RAG1 (Recombination Activating 1)
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    TMB-H • MSI-H/dMMR • TMB-L
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    dexamethasone
    9d
    Lung adenocarcinoma and colorectal cancer as double primary malignancies reveal lynch syndrome: a case report of germline MLH1 mutation with response to immunotherapy and familial aggregation. (PubMed, Front Immunol)
    This case highlights that lung adenocarcinoma can be a manifestation of LS and underscores the critical importance of retrospective MMR testing in establishing the diagnosis. Furthermore, it demonstrates the efficacy of immune checkpoint inhibitions in advanced dMMR tumors.
    Journal • PD(L)-1 Biomarker • IO biomarker
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    MLH1 (MutL homolog 1) • PMS2 (PMS1 protein homolog 2)
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    MSI-H/dMMR
    9d
    Results of a multigene panel testing approach targeting patients with suspected genetic predisposition to pancreatic ductal adenocarcinoma. (PubMed, Eur J Hum Genet)
    An exploratory approach consisting of unmasking the results of the NGS analysis of 123 « research » genes involved in the carcinogenesis was applied to the 447 patients tested negative for the different genes of our diagnostic panel. This approach failed to identify other susceptibility genes to pancreatic adenocarcinoma.
    Journal • BRCA Biomarker
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • STK11 (Serine/threonine kinase 11) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • PALB2 (Partner and localizer of BRCA2) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2) • APC (APC Regulator Of WNT Signaling Pathway) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D)
    10d
    A Trial of Regorafenib Plus Lorigerlimab in Patients With Locally Recurrent or Regrowing pMMR/MSS Localized Rectal Cancer (clinicaltrials.gov)
    P2, N=0, Withdrawn, M.D. Anderson Cancer Center | N=20 --> 0 | Trial completion date: Sep 2032 --> Jan 2026 | Initiation date: Apr 2026 --> Oct 2025 | Not yet recruiting --> Withdrawn | Trial primary completion date: Sep 2030 --> Jan 2026
    Enrollment change • Trial completion date • Trial initiation date • Trial withdrawal • Trial primary completion date • pMMR
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    MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2)
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    Stivarga (regorafenib) • lorigerlimab (MGD019)