Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study

Background: Constitutional mismatch-repair deficiency (CMMRD) is an aggressive cancer-predisposition syndrome caused by biallelic pathogenic variants in PMS2, MSH6, MLH1, and MSH2. Lack of robust data on the true clinical-spectrum, cancerbiology, and genotype-phenotype associations result in challenges in management and inferior patient outcomes. Methods: The International Replication-Repair Deficiency Consortium performed comprehensive clinical and molecular analyses for CMMRD patients longitudinally between 2008-2022 and investigated the impact of genotype and cancer-biology on patient survival. Findings: Data on 201 patients from 27 countries demonstrated high homozygosity in countries with low consanguinity, particularly among minorities. Dermatological manifestations were frequent (93%), with 28% fulfilling clinical criteria for neurofibromatosis-type-1. One-hundred-and-ninety-four (97%) patients developed 339 cancers, with cumulative cancer incidence reaching 90% by age-18 and 100% by age- 40. The 2nd-cancer incidence was 49% within 10-years after first cancer diagnosis. Median time to a new cancer was 2-years. An expanded neoplastic spectrum included previously unreported, and early-onset, adult-type, breast, prostate, and pancreatic cancers by the 3rd-decade. The cancers exhibited universal hypermutation, high microsatellite instability, and corresponding mutational signatures. A significant difference in mutational burden between cancer types was related to somatic mutations in POLE/POLD1 and TP53, which were enriched in brain tumors, contributing to poor 10-year survival (39%; p<0.0001). MLH1/MSH2 genotypes had an earlier cancer-onset than PMS2/MSH6, and inferior patient survival (15-years overall survival: PMS2: 63%, MSH6: 49%, MLH1: 19%,MSH2: 0%; p<0.0001). Truncating mutations resulted in earlier cancers and poor outcomes even within the same gene (p<0.0001). Although surveillance and immunotherapy improved outcomes, the deleterious impact of specific genotypes persisted. Interpretation: ...