Title: Homologous Recombination Repair Truncations Predict Hypermutation in Microsatellite Stable Colorectal and Endometrial Tumors.
Authors: Lee, Minyi; Eng, George; Barbari, Stephanie R; Deshpande, Vikram; Shcherbakova, Polina V; Gala, Manish K
Published In Clin Transl Gastroenterol, (2020 03)
Abstract: INTRODUCTION: Somatic mutations in BRCA1/2 and other homologous recombination repair (HRR) genes have been associated with sensitivity to PARP inhibitors and/or platinum agents in several cancers, whereas hypermutant tumors caused by alterations in POLE or mismatch repair genes have demonstrated robust responses to immunotherapy. We investigated the relationship between somatic truncations in HRR genes and hypermutation in colorectal cancer (CRC) and endometrial cancer (EC). METHODS: We analyzed the mutational spectra associated with somatic BRCA1/2 truncations in multiple genomic cohorts (N = 2,335). From these results, we devised a classifier incorporating HRR genes to predict hypermutator status among microsatellite stable (MSS) tumors. Using additional genomic cohorts (N = 1,439) and functional in vivo assays, we tested the classifier to disambiguate POLE variants of unknown significance and identify MSS hypermutators without somatic POLE exonuclease domain mutations. RESULTS: Hypermutator phenotypes were prevalent among CRCs with somatic BRCA1/2 truncations (50/62, 80.6%) and ECs with such mutations (44/47, 93.6%). The classifier predicted MSS hypermutators with a cumulative true-positive rate of 100% in CRC and 98.0% in EC and a false-positive rate of 0.07% and 0.63%. Validated by signature analyses of tumor exomes and in vivo assays, the classifier accurately reassigned multiple POLE variants of unknown significance as pathogenic and identified MSS hypermutant samples without POLE exonuclease domain mutations. DISCUSSION: Somatic truncations in HRR can accurately fingerprint MSS hypermutators with or without known pathogenic exonuclease domain mutations in POLE and may serve as a low-cost biomarker for immunotherapy decisions in MSS CRC and EC.
PubMed ID: 32352724
MeSH Terms: Antineoplastic Agents/pharmacology*; Antineoplastic Agents/therapeutic use; BRCA1 Protein/genetics; BRCA2 Protein/genetics; Biomarkers, Tumor/genetics*; Clinical Decision-Making/methods; Colorectal Neoplasms/drug therapy*; Colorectal Neoplasms/genetics; Colorectal Neoplasms/pathology; DNA Mismatch Repair/drug effects; DNA Mismatch Repair/genetics; DNA Mutational Analysis/methods; DNA Polymerase II/genetics; Datasets as Topic; Drug Resistance, Neoplasm/genetics; Endometrial Neoplasms/drug therapy*; Endometrial Neoplasms/genetics; Endometrial Neoplasms/pathology; Female; Humans; Male; Microsatellite Instability; Microsatellite Repeats/genetics; Mutation; Poly-ADP-Ribose Binding Proteins/genetics; Recombinational DNA Repair/drug effects; Recombinational DNA Repair/genetics*; Whole Exome Sequencing