43. Association between Clonal Hematopoiesis and Inherited Cancer Susceptibility Genes

Abstract

<h3>Background</h3> Understanding how germline mutations affect Clonal Hematopoiesis (CH) will provide insights into germline predisposition to MN. <h3>Methods</h3> We leveraged blood whole-exome sequencing data from 200,643 individuals in the UK Biobank (UKBB). The association between CH and germline mutations in 211 cancer susceptibility genes were tested among participants without hematologic malignancies at baseline using logistic regression adjusted for known confounders. Genes suggestive of association with CH were validated in 17,037 solid tumor patients with blood sequenced using Memorial Sloan Kettering (MSK) IMPACT panel. <h3>Results</h3> Germline pathogenic/likely pathogenic mutations were detected in 8,967 UKBB participants (4.5%). Germline mutations in TP53, ATR, ATM, and MPL were associated with increased risk of CH with odds ratios (ORs) and confidence intervals (CIs) of 4.33(1.31-14.32), 2.53(1.11-5.76), 2.21(1.23-3.97) and 1.44(1.00-2.08), correspondingly. Among 37 subjects with Li Fraumeni in the MSK-IMPACT cohort, TP53 was also associated with CH (OR: 3.75, 95% CI: 1.40-8.94) and this association was independent of cancer therapy (ORuntreated: 13.52, 95% CI: 2.94-57.48). The significant positive associations between germline TP53 mutations and CH were driven by somatic mutations in TP53 (OR:18.5, 95% CI: 2.8-72.8) and DNMT3A (OR: 5.1, 95% CI: 1.8-12.4). The rate of MN in TP53 mutation carriers was significantly increased (incidence rate ratio: 23.3; 95% CI: 6.0-65.4). The transition to MN was demarcated by a second TP53 loss of function mutation or deletion and by complex karyotype. <h3>Conclusions</h3> Germline mutations in cancer susceptibility genes, particularly those in the DNA damage response pathway are independent risk factors for CH and MN development.