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    GENE:

    MLH1 (MutL homolog 1)

    i
    Other names: MLH1, COCA2, FCC2, HNPCC, HNPCC2, MutL homolog 1
    4d
    The Relationship of Microsatellite Instability with BRAF and p53 Mutations and Histopathological Parameters in Colorectal Adenocarcinoma. (PubMed, Ann Ital Chir)
    In colorectal adenocarcinoma, MSI and BRAF mutation are associated with parameters, indicating the host immune response and prognostic histopathological parameters, including tumor size and histological grade. The evaluation of MSI status and BRAF mutation can be particularly informative for predicting the prognosis and guiding the treatment management in poorly differentiated colorectal adenocarcinoma. Understanding the mechanisms of molecular carcinogenesis in colorectal carcinoma and organizing treatment algorithms based on molecular foundations will increase the success of the treatment.
    Journal • Microsatellite instability
    |
    BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2)
    |
    TP53 mutation • BRAF mutation • PMS2 mutation • BRAF mutation + TP53 mutation
    7d
    Microenvironment, systemic inflammatory response and tumor markers considering consensus molecular subtypes of colorectal cancer. (PubMed, Pathol Oncol Res)
    More routinely available TME, SIR and tumor markers alone and in combination deliver reliable prognostic data for choosing the patients with higher risk for propagation. CMS4 is linked with high TSR and poor prognosis, but in overall, CMS-classification showed only limited effect on SIR- and tumor-markers.
    Journal
    |
    MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • CEACAM5 (CEA Cell Adhesion Molecule 5) • PMS2 (PMS1 protein homolog 2) • CDX2 (Caudal Type Homeobox 2) • ZEB1 (Zinc Finger E-box Binding Homeobox 1) • CA 19-9 (Cancer antigen 19-9) • CRP (C-reactive protein) • FRMD6 (FERM Domain Containing 6) • HTR2B (5-Hydroxytryptamine Receptor 2B)
    8d
    Transvaginal Ultrasound and Photoacoustic Imaging of Ovary (clinicaltrials.gov)
    P=N/A, N=310, Recruiting, Washington University School of Medicine | Trial completion date: Jun 2030 --> Jan 2027 | Trial primary completion date: Jun 2030 --> Jan 2027
    Trial completion date • Trial primary completion date
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • EPCAM (Epithelial cell adhesion molecule) • BARD1 (BRCA1 Associated RING Domain 1)
    |
    BARD1 mutation
    8d
    Clinicopathological Implications of Mismatch Repair Status in Endometrioid Endometrial Cancer in Duhok City. (PubMed, Cureus)
    The majority of the recruited EC patients in this study showed advanced age and a high percentage of d-MMR status.
    Journal • Mismatch repair
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    MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2)
    |
    MSI-H/dMMR
    9d
    Nivolumab + Docetaxel + ADT in mHSPC Patients With DDRD or Inflamed Tumors (clinicaltrials.gov)
    P2, N=60, Active, not recruiting, Xiao X. Wei, MD | Recruiting --> Active, not recruiting
    Enrollment closed • Combination therapy • Metastases
    |
    PD-L1 (Programmed death ligand 1) • BRCA1 (Breast cancer 1, early onset) • MSI (Microsatellite instability) • CD8 (cluster of differentiation 8) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • ABRAXAS1 (Abraxas 1 BRCA1 A Complex Subunit 2) • GEN1 (GEN1 Holliday junction 5' flap endonuclease)
    |
    PD-L1 expression • MSI-H/dMMR
    |
    OncoPanel™ Assay
    |
    Opdivo (nivolumab) • docetaxel • goserelin acetate • Firmagon (degarelix) • leuprolide acetate for depot suspension
    10d
    In vitro study of radiosensitivity in colorectal cancer cell lines associated with Lynch syndrome. (PubMed, Front Public Health)
    Overall, this study showed radio-resistance of the MMR proficient cell line in some assays, but not in the others. All methods used within this study have been validated; however, due to the limitations associated with cancer cell lines, the next step will be to use these assays in clinical samples in an effort to understand the biological and mechanistic effects of radiation in Lynch patients as well as the health implications.
    Preclinical • Journal
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    MLH1 (MutL homolog 1) • MSH2 (MutS Homolog 2)
    |
    MSI-H/dMMR
    11d
    Curative resection via right hemicolectomy and regional lymph node dissection for colonic adenomatous polyposis of unknown etiology with adenocarcinomas localized in the right side of the colon: a case report. (PubMed, Surg Case Rep)
    In this rare case, colonic adenomatous polyposis of unknown etiology, with numerous adenomatous polyps and multiple adenocarcinomas localized in the right side of the colon, was successfully treated with right hemicolectomy and regional lymph node dissection. Despite genetic analysis, no causative germline variants were identified. Segmental colectomy according to the distribution of polyps might be a curative approach.
    Journal
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    TP53 (Tumor protein P53) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2) • POLD1 (DNA Polymerase Delta 1) • EPCAM (Epithelial cell adhesion molecule) • MBD4 (Methyl-CpG Binding Domain 4, DNA Glycosylase) • MSH3 (MutS Homolog 3) • MUTYH (MutY homolog)
    13d
    Clinicopathological characteristics of Lynch-like syndrome. (PubMed, Int J Clin Oncol)
    Distinguishing clinically between LS and LLS was challenging, but the incidence of neoplasms was higher in LS than in LLS, suggesting the need for different screening and surveillance methods for the two subtypes.
    Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • MSI (Microsatellite instability) • MLH1 (MutL homolog 1)
    |
    KRAS wild-type • BRAF wild-type
    16d
    Outcomes of 10 years of PSA screening for prostate cancer in Norwegian men with Lynch syndrome. (PubMed, Prostate)
    Our results indicate that the MMR genes, and especially MSH2 and MSH6, are associated with a significant risk of PCa, and a high number of tumors show aggressive characteristics. While the impact of screening on patient outcomes remains to be more firmly established, the high SIR values we observe provide support for continued PSA screening of MSH2 and MSH6 carriers. Studies are needed to provide optimal recommendations for PSA-threshold and to evaluate whether MLH1 and PMS2 carriers should not be recommended screening.
    Journal • MSi-H Biomarker
    |
    MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2)
    |
    MSI-H/dMMR
    18d
    Cancer Preventive Vaccine Nous-209 for Lynch Syndrome Patients (clinicaltrials.gov)
    P1/2, N=60, Recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2025 --> Jul 2025 | Trial primary completion date: Mar 2025 --> Jul 2025
    Trial completion date • Trial primary completion date
    |
    BRAF (B-raf proto-oncogene) • MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2)
    |
    BRAF mutation • MSH2 mutation • MLH1 mutation • PMS2 mutation
    |
    NOUS-209
    19d
    Incidence and molecular characteristics of deficient mismatch repair conditions across nine different tumors and identification of germline variants involved in Lynch-like syndrome. (PubMed, Int J Clin Oncol)
    Our data regarding the LS to LLS ratio would be useful for genetic counseling in patients who are suspected to have LS, though the genetic backgrounds for the pathogenesis of LLS need further investigation.
    Journal • Mismatch repair • BRCA Biomarker
    |
    BRCA1 (Breast cancer 1, early onset) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2)
    |
    MSI-H/dMMR
    20d
    Expression of immune checkpoints PD-L1, CTLA4, LAG3 in the microenvironment of colon adenocarcinoma depending on MMR status (PubMed, Arkh Patol)
    A study using multiplex immunohistochemical analysis showed that MMR-deficient colon adenocarcinomas are characterized by more pronounced immune infiltration and increased expression of immune checkpoints in microenvironmental cells, mainly in the area of invasive tumor growth. The data obtained may be important for understanding the mechanisms of immune-mediated control of tumor growth and the choice of immunotherapy tactics depending on MMR status.
    Journal • PD(L)-1 Biomarker • IO biomarker
    |
    PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • MLH1 (MutL homolog 1) • LAG3 (Lymphocyte Activating 3) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2) • CD163 (CD163 Molecule)
    |
    PD-L1 expression • MSI-H/dMMR • LAG3 expression • CTLA4 expression
    21d
    APRISE Program - Australian Pancreatic High-RIsk ScrEening Program for individuals who are at high risk of developing pancreatic cancer due to familial or genetic risk factors (ACTRN12624000421538)
    P=N/A, N=500, Not yet recruiting, Epworth HealthCare
    New trial
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • STK11 (Serine/threonine kinase 11) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2)
    24d
    Comparison of Microsatellite Instability With Clinicopathologic Data in Patients With Colon Adenocarcinoma. (PubMed, Cureus)
    Identifying MSI in CRCs may help personalize therapy planning. As the distribution of the features may vary from population to population, further investigations are needed on this topic.
    Journal • Microsatellite instability
    |
    MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • PMS2 (PMS1 protein homolog 2)
    |
    MSI-H/dMMR
    26d
    Mitotic abnormalities precede microsatellite instability in lynch syndrome-associated colorectal tumourigenesis. (PubMed, EBioMedicine)
    The results validate our previous findings from mice and highlight early mitotic abnormalities as an important contributor and precancerous marker of colorectal tumourigenesis in LS.
    Journal • Microsatellite instability
    |
    MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2)
    |
    MSH6 mutation • MSH2 mutation • MLH1 mutation
    27d
    Genomic ancestry and cancer among Latin Americans. (PubMed, Clin Transl Oncol)
    Due to the complexity of genetic divergence, inputs from each individual ancestry seem to carry independent contributions that interplay in the development of these complex disease phenotypes. By understanding these unique population characteristics, genomic ancestries hold a promising avenue for tailoring prognostic assessments and optimizing responses to oncological interventions.
    Journal • BRCA Biomarker
    |
    EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MLH1 (MutL homolog 1)
    |
    KRAS mutation • BRCA2 mutation • BRCA1 mutation • EGFR mutation • HER-2 mutation • EGFR mutation + KRAS mutation
    28d
    Surviving without BRCA2: MLH1 gets R-looped in to curtail genomic instability. (PubMed, J Clin Invest)
    Moreover, MLH1 expression was regulated directly by estrogen, shedding light into the hormone-responsive nature of many BRCA2 mutant breast cancers. These results provide important insight into the genetics that drive the initiation of BRCA2-mutated breast cancers.
    Journal • BRCA Biomarker
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    BRCA2 (Breast cancer 2, early onset) • MLH1 (MutL homolog 1)
    |
    BRCA2 mutation
    28d
    High expression of NOTCH2 in gastric adenocarcinoma: A novel early diagnostic target. (PubMed, J Gastroenterol Hepatol)
    Our findings suggested that NOTCH2 may be a potential diagnostic target for GC due to the fact that its high expression is closely associated with the early stages of cancer.
    Journal
    |
    HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2) • NOTCH2 (Notch 2)
    29d
    Combination Chemotherapy With or Without Atezolizumab in Treating Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair (clinicaltrials.gov)
    P3, N=700, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Apr 2024 --> Apr 2025 | Trial primary completion date: Apr 2024 --> Apr 2025
    Trial completion date • Trial primary completion date • Mismatch repair • Tumor mutational burden
    |
    MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • CD4 (CD4 Molecule)
    |
    MSI-H/dMMR • MSH2 mutation • MLH1 mutation • PMS2 mutation • MSH6 expression
    |
    Tecentriq (atezolizumab) • oxaliplatin • leucovorin calcium • fluorouracil topical
    29d
    An Intervention to Increase Genetic Testing in Families Who May Share a Gene Mutation Related to Cancer Risk (clinicaltrials.gov)
    P=N/A, N=2590, Recruiting, Memorial Sloan Kettering Cancer Center | N=896 --> 2590
    Enrollment change
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • SMAD4 (SMAD family member 4) • CHEK2 (Checkpoint kinase 2) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • POLD1 (DNA Polymerase Delta 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • EPCAM (Epithelial cell adhesion molecule) • BARD1 (BRCA1 Associated RING Domain 1) • BMPR1A (Bone Morphogenetic Protein Receptor Type 1A)
    30d
    Methylation study of tumor suppressor genes in human aberrant crypt foci, colorectal carcinomas, and normal colon. (PubMed, J Cancer Res Ther)
    Early epigenetic methylation of WIF1 gene is one of the mechanisms for ACF development in human colon.
    Journal
    |
    CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MLH1 (MutL homolog 1) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • CD44 (CD44 Molecule) • RASSF1 (Ras Association Domain Family Member 1) • WIF1 (WNT Inhibitory Factor 1)
    |
    CD44 expression • CD44 positive • RASSF1 methylation
    1m
    Testing region selection and prognostic analysis of MLH1 promoter methylation in colorectal cancer in China. (PubMed, Gastroenterol Rep (Oxf))
    Regions D and E in the MLH1 promoter are recommended for determining the MLH1 methylation status in screening for LS in MLH1-deficient CRC. In MMR-deficient patients, the MLH1-methylated cases had a worse OS than the unmethylated cases with a family history of LS-related cancer.
    Journal
    |
    MLH1 (MutL homolog 1)
    |
    BRAF V600E • BRAF V600
    1m
    Immunoexpression of Mismatch Repair Proteins in a Cohort of Colorectal Cancer Patients. (PubMed, Curr Health Sci J)
    The highest values of the MSH2 and MSH6 scores were observed in mucinous tumors, and poorly differentiated lesions, in stages II-III, and stages III-IV, respectively. To improve the stratification criteria for targeted oncological therapy and to predict patient outcomes, markers used may help evaluate the aggressiveness of lesions.
    Journal • Mismatch repair
    |
    MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2)
    1m
    Mismatch repair protein deficiency and its implications on distant metastasis in colorectal cancer: A comprehensive analysis. (PubMed, Cancer Med)
    Geographical and ethnic factors might influence peculiarities in MMR protein loss. Our findings also highlight new gene expression networks and crucial regulatory molecules in CRC metastasis, enhancing our comprehension of the mechanisms driving distant metastasis.
    Journal • Mismatch repair
    |
    MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2) • IRF1 (Interferon Regulatory Factor 1)
    |
    MSI-H/dMMR • IRF1 expression • MSH6 expression
    1m
    A Pancreatic Cancer Screening Study in Hereditary High Risk Individuals (clinicaltrials.gov)
    P=N/A, N=200, Recruiting, Nuvance Health | N=100 --> 200
    Enrollment change
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2)
    |
    BRCA1 mutation • ATM mutation • PALB2 mutation • CDKN2A mutation • MSH2 mutation • PMS2 mutation
    1m
    Exploring the combined anti-cancer effects of sodium butyrate and celastrol in glioblastoma cell lines: a novel therapeutic approach. (PubMed, Med Oncol)
    These findings indicate that SB and CEL may act through multiple mechanisms, including DNA repair inhibition, apoptosis induction, and autophagy modulation, to exert their anti-cancer effects in glioblastoma cells. This is the first study providing novel insights into the potential therapeutic effects of SB and CEL in glioblastoma.
    Preclinical • Journal
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    MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • CASP3 (Caspase 3) • CASP8 (Caspase 8) • CASP9 (Caspase 9)
    1m
    Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study. (PubMed, Lancet Oncol)
    The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD.
    Journal • Mismatch repair • IO biomarker
    |
    MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2)
    |
    MSH2 mutation • MLH1 mutation • PMS2 mutation
    1m
    The Phoenix Trial: Phase II Trial of Cemiplimab for the Non-operative Management of Localized dMMR Colon Cancer (clinicaltrials.gov)
    P2, N=50, Not yet recruiting, M.D. Anderson Cancer Center | Trial completion date: Apr 2027 --> Apr 2028 | Initiation date: Jan 2024 --> Jan 2025 | Trial primary completion date: Apr 2025 --> Apr 2026
    Trial completion date • Trial initiation date • Trial primary completion date • Tumor mutational burden
    |
    MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2)
    |
    MSI-H/dMMR
    |
    Libtayo (cemiplimab-rwlc)
    1m
    Microsatellite instability: A 2024 update. (PubMed, Cancer Sci)
    Therefore, clinical relevance exists for analyses of MSI and MSI-H-associated genomic alterations in malignancy. In this article, we provide an update on MSI-driven carcinogenesis, with an emphasis on unique landscapes of diagnostic and immunotherapeutic strategies.
    Review • Journal • Microsatellite instability • MSi-H Biomarker • IO biomarker
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • NTRK (Neurotrophic receptor tyrosine kinase)
    |
    MSI-H/dMMR • KRAS wild-type • BRAF wild-type • RAS wild-type • RAS wild-type + BRAF wild-type • NTRK fusion
    1m
    Epigenetic MLH1 silencing concurs with mismatch repair deficiency in sporadic, naturally occurring colorectal cancer in rhesus macaques. (PubMed, J Transl Med)
    These data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. We consider this spontaneous, uninduced CRC in immunocompetent, treatment-naïve rhesus macaques to be a uniquely informative model for human CRC.
    Journal • Mismatch repair • IO biomarker
    |
    KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • MSI (Microsatellite instability) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • ARID1A (AT-rich interaction domain 1A) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2) • AMER1 (APC Membrane Recruitment Protein 1) • NEUROG1 (Neurogenin 1) • TFAP2A (Transcription Factor AP-2 Alpha)
    |
    TP53 mutation • KRAS mutation • KRAS G12D • ARID1A mutation • KRAS G12 • TP53 R175H • MLH1 mutation
    1m
    Germline Cancer Susceptibility in Individuals with Melanoma. (PubMed, J Am Acad Dermatol)
    Germline predisposition in individuals with melanoma is common, with clinically actionable findings diagnosed in 10.6% to 15.8%.
    Journal • BRCA Biomarker
    |
    TP53 (Tumor protein P53) • BRCA2 (Breast cancer 2, early onset) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • BAP1 (BRCA1 Associated Protein 1) • MLH1 (MutL homolog 1) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2) • CHEK2 (Checkpoint kinase 2) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • MITF (Melanocyte Inducing Transcription Factor)
    1m
    SU2C ACT3: Identification and Treatment Of Micrometastatic Disease in Stage III Colon Cancer (clinicaltrials.gov)
    P3, N=400, Recruiting, Massachusetts General Hospital | Trial completion date: Apr 2026 --> Dec 2027 | Trial primary completion date: Apr 2025 --> Dec 2026
    Trial completion date • Trial primary completion date • Metastases
    |
    BRAF (B-raf proto-oncogene) • MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2)
    |
    BRAF V600E • MSI-H/dMMR • BRAF V600 • MSH6 expression
    |
    Opdivo (nivolumab) • Herceptin (trastuzumab) • Erbitux (cetuximab) • 5-fluorouracil • Perjeta (pertuzumab) • Mektovi (binimetinib) • Braftovi (encorafenib) • irinotecan • leucovorin calcium
    1m
    CHOMP: A Study of CHeckpoint Inhibitors in Men With prOgressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation (clinicaltrials.gov)
    P2, N=30, Recruiting, VA Office of Research and Development | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Mar 2024 --> Mar 2025
    Trial completion date • Trial primary completion date • Checkpoint inhibition • Mismatch repair • Metastases
    |
    EGFR (Epidermal growth factor receptor) • MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • CDK12 (Cyclin dependent kinase 12) • PMS1 (PMS1 protein homolog 1)
    |
    MSI-H/dMMR
    |
    Keytruda (pembrolizumab) • abiraterone acetate
    1m
    The effects of thymidylate synthase 3'UTR genotype on methylation of tumor-specific genes promoter in 22 colorectal cancer patients from southern Iran. (PubMed, Mol Biol Res Commun)
    Moreover, promoter methylation status was not dependent on DNMTs gene expression. Large sample size studies may contribute to validate these findings.
    Journal
    |
    MLH1 (MutL homolog 1) • MSH2 (MutS Homolog 2) • CDH1 (Cadherin 1) • TYMS (Thymidylate Synthetase) • MMP2 (Matrix metallopeptidase 2) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
    |
    MMP2 overexpression
    1m
    MRE11A: a novel negative regulator of human DNA mismatch repair. (PubMed, Cell Mol Biol Lett)
    Our findings reveal that MRE11A is a negative regulator of human MMR.
    Journal • Mismatch repair
    |
    MLH1 (MutL homolog 1) • PMS2 (PMS1 protein homolog 2) • MRE11A (MRE11 homolog, double strand break repair nuclease)
    2ms
    PancreasScan: Pancreatic Cancer Screening for At-risk Individuals (clinicaltrials.gov)
    P=N/A, N=500, Recruiting, Beth Israel Deaconess Medical Center | Trial completion date: Jul 2026 --> Mar 2028 | Trial primary completion date: Jul 2025 --> Mar 2027
    Trial completion date • Trial primary completion date
    |
    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) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • BRCA (Breast cancer early onset) • EPCAM (Epithelial cell adhesion molecule) • PRSS1 (Serine Protease 1)
    |
    BRCA2 mutation • BRCA1 mutation • PALB2 mutation • CDKN2A mutation • MLH1 mutation • PMS2 mutation • BRCA mutation
    2ms
    Mismatch repair enzymes regulate telomere recombination in Saccharomycescerevisiae. (PubMed, Biochem Biophys Res Commun)
    Furthermore, our observations indicate that MMR activity is indispensable for its impact on telomere recombination. Collectively, these results contribute to a more comprehensive understanding of the role of MMR in telomere recombination.
    Journal • Mismatch repair
    |
    MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2)
    2ms
    Cancer Preventive Vaccine Nous-209 for Lynch Syndrome Patients (clinicaltrials.gov)
    P1/2, N=60, Recruiting, National Cancer Institute (NCI) | N=45 --> 60 | Trial completion date: Jul 2025 --> Mar 2025 | Trial primary completion date: Jul 2025 --> Mar 2025
    Enrollment change • Trial completion date • Trial primary completion date
    |
    BRAF (B-raf proto-oncogene) • MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2)
    |
    BRAF mutation • MSH2 mutation • MLH1 mutation • PMS2 mutation
    |
    NOUS-209
    2ms
    Clonal origin and genomic diversity in Lynch syndrome-associated endometrial cancer with multiple synchronous tumors: Identification of the pathogenicity of MLH1 p.L582H. (PubMed, Genes Chromosomes Cancer)
    Additionally, all tumors presented unique mutations in endometrial cancer-associated genes such as ARID1A and PIK3CA. In conclusion, we demonstrated clonal origin and genomic diversity in a Lynch syndrome-associated endometrial cancer, suggesting the importance of evaluating multiple sites in Lynch syndrome patients with synchronous tumors.
    Journal
    |
    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MSI (Microsatellite instability) • ARID1A (AT-rich interaction domain 1A) • MLH1 (MutL homolog 1)
    |
    PIK3CA mutation • ARID1A mutation
    2ms
    Cascade screening in HBOC and Lynch syndrome: guidelines and procedures in a UK centre. (PubMed, Fam Cancer)
    Overall close to one positive cascade test was generated per index case resulting in > 1000 risk reducing surgery operations. In Lynch syndrome slightly more cascade tests were performed in the first two years potentially reflecting the increased actionability in males with 42.2% of pre-symptomatic tests in males compared to 25.8% in BRCA1/2 (p < 0.0001).
    Journal • BRCA Biomarker
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2)
    2ms
    Histone H3K9 Lactylation Confers Temozolomide Resistance in Glioblastoma via LUC7L2-Mediated MLH1 Intron Retention. (PubMed, Adv Sci (Weinh))
    Temozolomide (TMZ) resistance remains the major obstacle in the treatment of glioblastoma (GBM). Of note, it is identified that a clinical anti-epileptic drug, stiripentol, which can cross the blood-brain barrier and inhibit lactate dehydrogenase A/B (LDHA/B) activity, acts as a lactylation inhibitor and renders GBM cells more sensitive to TMZ in vitro and in vivo. These findings not only shed light on the mechanism of lactylation in GBM TMZ resistance but also provide a potential combined therapeutic strategy for clinical GBM treatment.
    Journal
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    LDHA (Lactate dehydrogenase A) • MLH1 (MutL homolog 1)
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    temozolomide
    2ms
    A Phase IIa Randomized, Double-Blinded Clinical Trial of Naproxen or Aspirin for Cancer Immune Interception in Lynch Syndrome (clinicaltrials.gov)
    P2, N=40, Recruiting, M.D. Anderson Cancer Center | Phase classification: P2a --> P2
    Phase classification
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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 • MSH2 mutation • MLH1 mutation • PMS2 mutation
    |
    aspirin