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    BIOMARKER:

    PMS2 mutation

    i
    Other names: PMS2, PMS1 Homolog 2, Mismatch Repair System Component, PMS1 Homolog 2, Mismatch Repair Protein, Mismatch Repair Endonuclease PMS2, DNA Mismatch Repair Protein PMS2, PMS1 Protein Homolog 2, PMSL2, PMS2 Postmeiotic Segregation Increased 2, Postmeiotic Segregation Increased 2 Nirs Variant 6, PMS2 Postmeiotic Segregation Increased 2, HNPCC4, PMS2CL, MLH4
    Entrez ID:
    5395
    Related biomarkers:
    Expression
    Mutation
    CNA
    Others
    24h
    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
    24h
    Acolbifene Versus Low Dose Tamoxifen for the Prevention of Breast Cancer in Premenopausal Women at High Risk for Development of Breast Cancer (clinicaltrials.gov)
    P2, N=80, Not yet recruiting, National Cancer Institute (NCI) | Phase classification: P2a --> P2 | Initiation date: Mar 2024 --> Oct 2024
    Phase classification • Trial initiation date
    |
    TP53 (Tumor protein P53) • PTEN (Phosphatase and tensin homolog) • ATM (ATM serine/threonine kinase) • NF1 (Neurofibromin 1) • MSH6 (MutS homolog 6) • CDH1 (Cadherin 1) • CHEK2 (Checkpoint kinase 2) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • AGR2 (Anterior gradient 2)
    |
    TP53 mutation • ATM mutation • PTEN mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • RAD51D mutation • PMS2 mutation • BARD1 mutation • NBN mutation
    |
    tamoxifen • acolbifene
    11d
    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
    15d
    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
    17d
    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
    28d
    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
    28d
    Biomarker characterization in endometrial cancer in Europe: first survey data analysis from 69 pathological academic and hospital labs. (PubMed, Pathologica)
    Other markers (mainly p53 followed by POLE and PTEN) are investigated in particular in Spain and Switzerland in a consistent number of cases. Guidelines consultation and standardization of laboratory procedures are efficient means for EC prognostic risk stratification and improving the quality of care.
    Journal
    |
    BRAF (B-raf proto-oncogene) • MSI (Microsatellite instability) • PTEN (Phosphatase and tensin homolog) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2)
    |
    TP53 mutation • BRAF mutation • BRAF V600 • PMS2 mutation
    1m
    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
    1m
    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
    |
    MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2)
    |
    MSI-H/dMMR • MSH2 mutation • MLH1 mutation • PMS2 mutation
    |
    aspirin
    1m
    Mainstream Model of Genetic Testing for Prostate Cancer at a Large Tertiary Cancer Centre. (PubMed, Clin Genitourin Cancer)
    We report on the real-world characteristics of prostate cancer patients who underwent mainstream germline genetic testing. Personal history and family history of cancer cannot reliably stratify patients for the presence of pathogenic germline variants.
    Journal • BRCA Biomarker
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • PMS2 (PMS1 protein homolog 2) • CHEK2 (Checkpoint kinase 2) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • HOXB13 (Homeobox B13)
    |
    BRCA2 mutation • BRCA1 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • PMS2 mutation
    2ms
    GC 2nd Line Durvalumab(MEDI4736)/Tremelimumab Plus Paclitaxel Study (clinicaltrials.gov)
    P1/2, N=58, Completed, Asan Medical Center | Active, not recruiting --> Completed
    Trial completion
    |
    PD-L1 (Programmed death ligand 1) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • POLD1 (DNA Polymerase Delta 1) • MSH3 (MutS Homolog 3) • PMS1 (PMS1 protein homolog 1) • POLD2 (DNA Polymerase Delta 2)
    |
    MSI-H/dMMR • MSH2 mutation • MLH1 mutation • PD-L1 amplification • POLD1 mutation • MSH3 mutation • PMS2 mutation • MLH3 mutation • PMS1 mutation • POLD2 mutation
    |
    Imfinzi (durvalumab) • paclitaxel • Imjudo (tremelimumab)
    2ms
    Correlation of PTEN Alterations with Immunohistochemistry in POLE-Mutated and Mismatch Repair-Deficient Endometrial Carcinoma (USCAP 2024)
    In summary, PTEN IHC expression was retained in the majority of PTEN- and POLE-mutated ECs with frequent missense mutations in codon 130. Some codon 130 mutations (e.g., R130Q) are known to be associated with protein stability. Nearly half of PTEN-mutated MMR-d ECs were associated with PTEN expression (retained, reduced or subclonal loss).
    Mismatch repair
    |
    MSI (Microsatellite instability) • PTEN (Phosphatase and tensin homolog) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • PMS2 (PMS1 protein homolog 2)
    |
    MSI-H/dMMR • PTEN mutation • POLE mutation • PTEN expression • PMS2 mutation
    |
    Oncomine™ Comprehensive Assay v3M
    2ms
    Endometrial Cancers with Low Level Microsatellite Instability: Classification Pitfalls and Practical Recommendations for Assigning Mismatch Repair Status by Next Generation Sequencing with MSIsensor and Ancillary Tests (USCAP 2024)
    MSIsensor scores as low as 3.5% may represent true MMRd in EC tested by NGS. Further testing for MMRd is advised for MSIsensor scores between 3% and 30%, particularly if there is low tumor content or associated high TMB. In this setting, MMR IHC may have superior sensitivity for detection of MMRd compared to DNA-based assays.
    Microsatellite instability • Tumor mutational burden • IO biomarker • Next-generation sequencing • Mismatch repair
    |
    TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2)
    |
    TMB-H • POLE mutation • MSH6 mutation • MSH2 mutation • PMS2 mutation
    |
    Idylla™ MSI Test
    2ms
    Next-Generation Sequencing Experience of Colorectal Cancer at a Quebec Health Care Centre (USCAP 2024)
    Our study is concordant with larger CRC sequencing studies. Although, the main targetable mutations are covered by the Focus Panel, a considerable proportion of specimens had no identifiable mutations. As more treatments become available, more extensive panels are necessary.
    Next-generation sequencing
    |
    HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • PMS2 (PMS1 protein homolog 2)
    |
    KRAS mutation • BRAF mutation • PIK3CA mutation • HER-2 mutation • APC mutation • PMS2 mutation
    |
    Illumina Focus Panel
    2ms
    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 2024 --> Feb 2025 | Trial primary completion date: Feb 2024 --> Feb 2025
    Trial completion date • Trial primary completion date
    |
    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)
    |
    MSH2 mutation • MLH1 mutation • PMS2 mutation
    2ms
    Differential responses to immune checkpoint inhibitors are governed by diverse mismatch repair gene alterations. (PubMed, Clin Cancer Res)
    Patients with mutS co-loss experienced longer mOS in CRC and EC and better response to ICIs in CRC. Among all explored biomarkers, NAL was higher in mutS co-loss and may be a potential driving factor for the observed better outcomes. TMB did not reliably predict NAL.
    Journal • Checkpoint inhibition • Mismatch repair • Tumor mutational burden • IO biomarker
    |
    TMB (Tumor Mutational Burden) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2)
    |
    MSI-H/dMMR • PMS2 mutation
    2ms
    The new 2023 FIGO staging system for endometrial cancer: what is different from the previous 2009 FIGO staging system? (PubMed, J Gynecol Oncol)
    The 2023 staging system for EC subdivided stages I and II compared to the 2009 system. The 2023 system with molecular classification is a good predictor of survival.
    Journal
    |
    POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • PMS2 (PMS1 protein homolog 2)
    |
    TP53 mutation • POLE mutation • PMS2 mutation
    3ms
    Genotype-phenotype correlations in carriers of the PMS2 founder variant c.1831dup. (PubMed, Mol Genet Genomic Med)
    Our results suggest that the PMS2 c.1831dup PV represents a, probably ancient, founder mutation and is possibly associated with an earlier CRC diagnosis compared to other PMS2 PVs.
    Journal
    |
    PMS2 (PMS1 protein homolog 2)
    |
    PMS2 mutation
    3ms
    PD-L1 diffuse large B-cell lymphoma with extremely high mutational burden and microsatellite instability due to acquired PMS2 mutation. (PubMed, Cold Spring Harb Mol Case Stud)
    This report, while highlighting the extent of possible tumor heterogeneity across separate clonal expansions as well as possible syndromic B-cell neoplasia, supports the notion that, although rare, PD-L1 expression and associated states permissive of high mutational burden (such as mismatch repair gene loss of function/MSI) should be more routinely considered in DLBCLs. Appropriate testing may be predictive of outcome and inform the utility of targeted therapy in these genetically diverse and historically treatment-refractory malignancies.
    Journal • Tumor mutational burden • Microsatellite instability • PD(L)-1 Biomarker • IO biomarker
    |
    PD-L1 (Programmed death ligand 1) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • PMS2 (PMS1 protein homolog 2)
    |
    PD-L1 expression • TMB-H • PMS2 mutation
    3ms
    Cycling in Preventing Colorectal Cancer in Participants With Lynch Syndrome (clinicaltrials.gov)
    P=N/A, N=21, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Jan 2024 | Trial primary completion date: Dec 2024 --> Jan 2024
    Trial completion • Trial completion date • Trial primary completion date
    |
    MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • EPCAM (Epithelial cell adhesion molecule)
    |
    MSI-H/dMMR • MSH2 mutation • MLH1 mutation • PMS2 mutation
    4ms
    Cycling in Preventing Colorectal Cancer in Participants With Lynch Syndrome (clinicaltrials.gov)
    P=N/A, N=21, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024
    Trial completion date • Trial primary completion date
    |
    MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • EPCAM (Epithelial cell adhesion molecule)
    |
    MSI-H/dMMR • MSH2 mutation • MLH1 mutation • PMS2 mutation
    4ms
    A multicohort phase 2 trial of ADT, docetaxel plus nivolumab in patients with de novo metastatic hormone-sensitive prostate cancer enriched for inflamed tumors and DNA damage repair defects. (ASCO-GU 2024)
    After January 2022, the addition of standard of care abiraterone/prednisone was allowed after 7 months of study treatment at investigator discretion. Clinical trial information: NCT04126070.PD-L1 Combined Positive Score (CPS) ≥ 1 and/or CD T cell density ≥ 200. Homozygous deletions and/or deleterious mutations in a DDR gene, including and not limited to BRCA2, ATM, CHECK2, BRCA1, PALB2, RAD51D, ATR, NBN, PMS2, GEN1, MLH1, MSH2, MSH6, RAD51C, MRE11A, BRIP1, FAM175A, and CDK12.
    P2 data • Clinical • PD(L)-1 Biomarker • BRCA Biomarker • IO biomarker • Metastases
    |
    PD-L1 (Programmed death ligand 1) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • CD8 (cluster of differentiation 8) • PALB2 (Partner and localizer of BRCA2) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • CDK12 (Cyclin dependent kinase 12) • PMS2 (PMS1 protein homolog 2) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • MRE11A (MRE11 homolog, double strand break repair nuclease) • 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 • ATM mutation • PALB2 mutation • BRIP1 mutation • RAD51C mutation • RAD51D mutation • PMS2 mutation • MRE11A mutation • NBN mutation
    |
    OncoPanel™ Assay
    |
    Opdivo (nivolumab) • docetaxel • abiraterone acetate
    4ms
    Molecular and clinical characteristics of POLE/POLD1 alterations among patients with colorectal cancer. (ASCO-GI 2024)
    POLE/POLD1 mutations frequently co-exist with MSI-H disease in CRC. Patients with MSS-CRC harboring POLE/POLD1 mutations represent a smaller subgroup of CRC (~1%). The incidence of POLE/POLD1 somatic mutations was more common among patients with colon cancer than those with rectal cancer.
    Clinical • MSi-H Biomarker
    |
    MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2) • POLD1 (DNA Polymerase Delta 1)
    |
    MSI-H/dMMR • POLE mutation • MSH6 mutation • MSH2 mutation • MLH1 mutation • POLD1 mutation • PMS2 mutation • POLE mutation + POLD1 mutation
    4ms
    Liquid biopsy-based comprehensive genomic profiling to reveal mutational landscape in real-world patients with gastrointestinal cancer. (ASCO-GI 2024)
    This study elucidated the comprehensive mutational landscape of advanced gastrointestinal cancer through liquid biopsy, thereby contributing novel biomarkers for clinical diagnosis and facilitating targeted therapy mechanism investigations.
    Real-world evidence • Clinical • Tumor mutational burden • BRCA Biomarker • Liquid biopsy • Real-world • Biopsy
    |
    EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • ARID1A (AT-rich interaction domain 1A) • MLH1 (MutL homolog 1) • FGFR4 (Fibroblast growth factor receptor 4) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2) • FAT1 (FAT atypical cadherin 1) • EPCAM (Epithelial cell adhesion molecule) • ERCC5 (ERCC Excision Repair 5 Endonuclease 2)
    |
    EGFR mutation • HRD • MSH6 mutation • MSH2 mutation • MLH1 mutation • PMS2 mutation
    |
    PredicineCARE™
    4ms
    Fucoxanthin Inhibits Development of Sigmoid Colorectal Cancer in a PDX Model With Alterations of Growth, Adhesion, and Cell Cycle Signals. (PubMed, Cancer Genomics Proteomics)
    Fx suppresses development of human-like CRC tissues, especially through growth, adhesion, and cell cycle signals.
    Journal
    |
    TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • ARID1A (AT-rich interaction domain 1A) • PMS2 (PMS1 protein homolog 2) • PMS1 (PMS1 protein homolog 1) • DCN (Decorin)
    |
    TP53 mutation • PMS2 mutation
    5ms
    Diffuse Large B-Cell Lymphoma Has a Low Frequency of dMMR and High Frequencies of DNA Mismatch Repair Protein High Expression Associated with Lower T-Cell Infiltration (ASH 2023)
    This study revealed that high expression of MMR proteins is a common feature of DLBCL associated with lower tumor-infiltrating T cells, MYC and p53 overexpression, and context-dependent prognostic effects. In contrast, dMMR and loss of MMR proteins are infrequent and have no significant prognostic effects in DLBCL treated with standard chemoimmunotherapy. These results may have implications for understanding DLBCL biology and the low efficacy of PD-1 blockade immunotherapy in DLBCL.
    Mismatch repair • PD(L)-1 Biomarker • IO biomarker
    |
    MSI (Microsatellite instability) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2)
    |
    MSI-H/dMMR • MYC overexpression • MYC expression • MSH6 mutation • MLH1 mutation • PMS2 mutation • TP53 overexpression • MSH6 expression
    5ms
    A Comprehensive Study of Heterogeneous Mismatch Repair Expression in Solid Tumors Reveals Different Immunohistochemical Patterns and Distinct Genetic Mechanisms. (PubMed, Am J Surg Pathol)
    Our findings highlighted the importance of accurately interpreting heterogeneous MMR protein staining patterns for developing a more efficient personalized genetic investigation strategy.
    Journal • Mismatch repair • Tumor mutational burden
    |
    TMB (Tumor Mutational Burden) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2)
    |
    TMB-H • POLE mutation • MSH6 mutation • MSH2 mutation • MLH1 mutation • PMS2 mutation • POLE EDM
    5ms
    Pilot Study of Nivolumab in Pediatric Patients With Hypermutant Cancers (clinicaltrials.gov)
    P1/2, N=11, Terminated, The Hospital for Sick Children | N=50 --> 11 | Trial completion date: Sep 2022 --> Nov 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Sep 2022 --> Nov 2023; Withdrawal of drug supply/funding
    Enrollment change • Trial completion date • Trial termination • Trial primary completion date • IO biomarker
    |
    TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • POLD1 (DNA Polymerase Delta 1) • EPCAM (Epithelial cell adhesion molecule) • MSH3 (MutS Homolog 3) • APOB (Apolipoprotein B)
    |
    MSI-H/dMMR • POLE mutation • MSH2 mutation • POLD1 mutation • PMS2 mutation • EPCAM expression
    |
    Opdivo (nivolumab)
    5ms
    Comparison of gene mutation profile in different lung adenocarcinoma subtypes by targeted next-generation sequencing. (PubMed, Med Oncol)
    This study revealed the heterogeneity of gene mutations and significantly altered pathways between different lung cancer subtypes, suggesting the potential mechanism of different prognosis.
    Journal • Next-generation sequencing
    |
    EGFR (Epidermal growth factor receptor) • TP53 (Tumor protein P53) • ARID1A (AT-rich interaction domain 1A) • KIF5B (Kinesin Family Member 5B) • PMS2 (PMS1 protein homolog 2)
    |
    TP53 mutation • EGFR mutation • ARID1A mutation • MTOR mutation • PMS2 mutation
    5ms
    Comparative Analysis of Mutational Patterns in Triple Negative Breast Cancer Before and after Neoadjuvant Chemotherapy in Patients with Residual Disease. (PubMed, Gene)
    We employed K-means clustering to categorize the patients based on their variant profiles, aiding in the prediction of possible patterns associated with recurrence. Our study was limited by its small sample size and retrospective design, suggesting the need for further validation in larger prospective cohorts.
    Journal • Tumor mutational burden
    |
    HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • PTEN (Phosphatase and tensin homolog) • NOTCH1 (Notch 1) • PMS2 (PMS1 protein homolog 2)
    |
    AR mutation • PMS2 mutation
    5ms
    Prognostic impact of tumor mutational burden at baseline in IDH-wildtype glioblastoma (SNO 2023)
    In summary, there is no significant association between TMB at baseline and poor survival outcomes in IDH-wildtype GBM. Further research is needed to explore the potential implications of TMB as a prognostic marker and its relevance for personalized treatment strategies in GBM patients.
    Tumor mutational burden
    |
    TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2)
    |
    MSH2 mutation • MLH1 mutation • PMS2 mutation • IDH wild-type
    |
    OncoPanel™ Assay
    5ms
    DEFINING THE IMPACT OF PERSONAL AND FAMILY HISTORY OF LYNCH-SYNDROME ASSOCIATED CANCERS ON CLINICAL CHARACTERISTICS AND OUTCOMES OF PATIENTS WITH UPPER TRACT UROTHELIAL CARCINOMA (SUO 2023)
    Factors that may be associated with lower complete and partial response in the NAC and higher risk of metastatic recurrence in the AC cohorts included history of Lynch, smoking history, and preoperative hydronephrosis whereas cisplatin-based chemotherapy may be associated with better outcomes (Table 2)... LS-related UTUC may have distinct biologic behavior and responses to chemotherapy than sporadic UTUC. Given the superior outcomes seen with immunotherapy in metastatic disease and the approved indication for this treatment in those with LS, proper identification of LS-related UTUC is imperative in order to evaluate this paradigm further in the non-metastatic setting. This can be most reliably achieved with universal tumor testing and confirmatory germline sequencing.
    Clinical • IO biomarker
    |
    MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2)
    |
    MSH2 mutation • MLH1 mutation • PMS2 mutation
    |
    cisplatin
    5ms
    Unique molecular signatures of germline mutations in low expression of human epidermal growth factor receptor 2 (HER2) breast cancer (SABCS 2023)
    HER2-low BC patients have distinct germline mutational signatures and differential clinical outcomes under neoadjuvant systemic therapy. These results have provided additional evidence that HER2-low patients comprise a fourth subtype of BC that needs to be accounted for separately in terms of clinical treatment and outcome reporting.
    BRCA Biomarker
    |
    HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • ATM (ATM serine/threonine kinase) • HRD (Homologous Recombination Deficiency) • PALB2 (Partner and localizer of BRCA2) • MSH2 (MutS Homolog 2) • ERCC1 (Excision repair cross-complementation group 1) • PMS2 (PMS1 protein homolog 2) • CHEK2 (Checkpoint kinase 2) • FANCA (FA Complementation Group A) • RAD51C (RAD51 paralog C) • MRE11A (MRE11 homolog, double strand break repair nuclease) • MUTYH (MutY homolog) • FANCI (FA Complementation Group I) • FANCM (FA Complementation Group M) • FLCN (Folliculin) • FANCD2 (FA Complementation Group D2) • RECQL4( RecQ Like Helicase 4) • BMPR1A (Bone Morphogenetic Protein Receptor Type 1A) • RAD54B (RAD54 Homolog B)
    |
    BRCA1 mutation • EGFR mutation • HER-2 overexpression • HER-2 mutation • HER-2 expression • ATM mutation • PALB2 mutation • MSH2 mutation • RAD51C mutation • FANCA mutation • PMS2 mutation • FANCI mutation • FANCM mutation • RAD51 mutation • RECQL4 mutation
    5ms
    Exceptional long-term disease control on pembrolizumab monotherapy in a patient with TMB-high PMS2-mutated MMR-deficient triple negative breast cancer brain metastasis (SABCS 2023)
    She underwent partial mastectomy, axillary dissection, radiation, and received adjuvant anastrozole...She received adjuvant chemotherapy (AC-T) and 1 year of trastuzumab...Two years later, concern for progression from rising tumor markers led to addition of concurrent carboplatin/gemcitabine for 5 cycles...Altogether, this case is a remarkable addition to growing evidence that TMB could be a biomarker for predicting response to ICI therapy and provides an example of ICI efficacy in the setting of BCBM. Further research on additional genomic, clinical, and pathologic features associated with ICI responsiveness is warranted for greater precision in BCBM management.
    Clinical • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker
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    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor) • TMB (Tumor Mutational Burden) • PMS2 (PMS1 protein homolog 2)
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    HER-2 positive • TMB-H • ER negative • ER positive + PGR positive • PMS2 mutation • PGR negative
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    Keytruda (pembrolizumab) • Herceptin (trastuzumab) • carboplatin • gemcitabine • anastrozole
    5ms
    The MAGIC study: Universal whole genome tumour and germline sequencing of newly diagnosed breast cancer identifies a high proportion of ER+ BRCA-like tumours (SABCS 2023)
    Tumour sequencing identified three times as many cases that might be eligible for HR repair defect targeted therapy than germline testing alone (16% versus 5.2%). Unlike a previous study (Ann Oncol., 2019 30:1071-1079), the majority of the BRCA-like BCs were ER+ with no evidence of a VUS in a known HBC gene suggesting these are driven by novel germline or somatic mutations in genes involved in DNA HR repair.
    BRCA Biomarker
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    ER (Estrogen receptor) • 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) • HRD (Homologous Recombination Deficiency) • PALB2 (Partner and localizer of BRCA2) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2) • BRCA (Breast cancer early onset) • CDH1 (Cadherin 1) • CHEK2 (Checkpoint kinase 2) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • BARD1 (BRCA1 Associated RING Domain 1)
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    ER positive • BRCA1 mutation • HRD • PALB2 mutation • HRD + BRCA1 mutation • RAD51C mutation • PMS2 mutation • RAD51 mutation
    5ms
    Clonal Hematopoiesis Is Associated with Severe Cytokine Release Syndrome in Patients Treated with Chimeric Antigen Receptor T-Cell (CAR-T) Therapy (ASH 2023)
    All received fludarabine and cyclophosphamide for lymphodepleting chemotherapy. Axicabtagene ciloleucel was the most common (76%) CAR-T product, followed by tisagenlecleucel in 16% of patients... CH was frequent (24%) in this cohort of CAR-T recipients and was associated with a higher risk of ≥2 CRS after CAR-T. Additional validation studies are currently underway, which may set the stage for consideration of pre-CAR-T CH as a biomarker for risk stratification towards more proactive CRS prophylaxis Acknowledgements: Funding through the CoH Hematological Malignancies Program Pilot Project Award. The authors acknowledge the work provided by CoH Center for Informatics, notably Research Informatics, and the utilization of the POSEIDON platform and the Honest Broker process.
    Clinical • CAR T-Cell Therapy • IO biomarker
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    DNMT3A (DNA methyltransferase 1) • ASXL1 (ASXL Transcriptional Regulator 1) • PMS2 (PMS1 protein homolog 2) • CHEK2 (Checkpoint kinase 2)
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    DNMT3A mutation • ASXL1 mutation • CHEK2 mutation • PMS2 mutation
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    cyclophosphamide • Yescarta (axicabtagene ciloleucel) • Kymriah (tisagenlecleucel-T) • fludarabine IV
    5ms
    Routine Whole Genome Sequencing for All Children with Hematological Malignancies Defines a New Standard of Care - Data of the First 152 Cases from the NHS England Genomic Medicine Service (ASH 2023)
    In the case of the most common childhood malignancy, ALL, one test can replace all diagnostics, including IG/TCR MRD marker screening and pharmacogenomics for TPMT/NUDT15. With continued improvements in turnaround time, and reducing costs, we propose that WGS could feasibly replace multiple molecular diagnostic tests for pediatric hematological malignancies.
    Clinical • Whole genome sequencing
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    TP53 (Tumor protein P53) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • ETV6 (ETS Variant Transcription Factor 6) • PMS2 (PMS1 protein homolog 2) • DUX4 (Double Homeobox 4) • NUDT15 (Nudix Hydrolase 15)
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    TP53 mutation • RAS mutation • PMS2 mutation
    5ms
    Clinical and Molecular Characterization of Patients with Therapy Related Myeloid Neoplasms (TRMN) (ASH 2023)
    Our results highlight the role of mutations in cancer predisposition genes in the development of TRMN. Similar latency associations were found for TRMN and nTMN patients, which suggest that other risk factors different than treatment might contribute to the TRMN development. Altered karyotypes in TRMN patients are associated with acquired mutations in myeloid genes but not with germline mutations, which suggests two different entities with different prognosis.
    Clinical • BRCA Biomarker
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    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) • CHEK2 (Checkpoint kinase 2)
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    CHEK2 mutation • Chr del(5q) • PMS2 mutation
    5ms
    The Relapse Mechanisms and Genomic Landscape Differ in KMT2A-r Pediatric Leukemia in Relation to Relapse Time (ASH 2023)
    By contrast, early relapse ALL was characterized by a single diagnostic clone seeding relapse by a clonal sweep along with acquired mutations in chemoresistance-associated genes. To validate and extend these findings, we are currently analyzing 11 additional infant relapse samples with WGS.
    Clinical • Tumor mutational burden
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    TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • KMT2A (Lysine Methyltransferase 2A) • IKZF1 (IKAROS Family Zinc Finger 1) • PMS2 (PMS1 protein homolog 2) • WT1 (WT1 Transcription Factor) • CREBBP (CREB binding protein) • NT5C2 (5'-Nucleotidase Cytosolic II) • CCND3 (Cyclin D3)
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    TP53 mutation • MLL rearrangement • PMS2 mutation • MLL fusion
    6ms
    Evaluation of Three Methods for Lynch Syndrome Screening in Patients with Colorectal Cancer (AMP 2023)
    The Promega OncoMate MSI Dx analysis system shows excellent concordance with the previous Promega MSI analysis system v1.2 and MMR IHC in CRC tumor samples, and has clinical utility in screening for LS in CRC patients.
    Clinical • MSi-H 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 • MSH2 mutation • MLH1 mutation • PMS2 mutation
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    OncoMate™ MSI