Abstract
Abstract BACKGROUND Constitutional mismatch repair deficiency (CMMRD) is an aggressive cancer predisposition syndrome. As a lack of data contributes to management challenges and inferior outcomes, especially in central nervous system (CNS) cancers, we aimed to determine the clinical spectrum, cancer biology, and impact of genetics on patient survival. METHODS To determine the cancer spectrum, biology, estimated incidence, and impact of genotype on cancer onset and survival, including following surveillance and immunotherapy, we collected cross-sectional, longitudinal, and genomic data on CMMRD patients and their cancers registered to an international consortium. RESULTS We report 201 patients enrolled between 2007-2022 (median follow-up: 7.2 years). Overall, 194 (97%) patients developed 339 cancers. Cumulative cancer and CNS tumor incidence were 93% and 82% by age 20, respectively. Median time between cancers was 2 years. Although neoplasms developed in 15 organs and included early-onset adult cancers, CNS tumors had the earliest median age of diagnosis (9.7 years), were the most common cancer type (51%), and the main cause of death (p<0.0001). All cancers exhibited high mutation and microsatellite burden, and pathognomonic mutational signatures. CNS cancers were enriched for mutations in POLE/POLD1, TP53, IDH1, and RAS/MAPK compared to hematopoietic and other cancers. These mutations determined response to therapy. Germline MLH1/MSH2 variants caused earlier cancer and CNS tumor onset than PMS2/MSH6, and inferior survival (survival at 15 years: PMS2: 63%, MSH6: 49%, MLH1: 19%, MSH2: 0%, p<0.0001). Strikingly, frameshift/truncating variants within the same gene caused earlier cancers and inferior outcomes (p<0.0001). The deleterious impact of MLH1/MSH2 persisted despite overall improvement in survival following surveillance and immunotherapy. CONCLUSION The extreme cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis focusing on specific genotypes to perform precision approaches toward surveillance and immunotherapy. These data will guide the management of children and emerging adult survivors of CMMRD.
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