Associations of tumor somatic mutations with cancer-associated venous thromboembolism.

Venous thromboembolism (VTE) is a common complication of cancer. Complex interactions between tumor biology and the hemostatic system contribute to development of cancer-associated thrombosis. This study examined associations of somatic mutations with VTE in a large multicancer cohort. We analyzed paired tumor and germline whole genome sequence data and electronic health records from 12 507 cancer patients recruited to the Genomics England National Genomic Research Library, to evaluate associations of somatic mutations across 608 genes, tumor mutational burden (TMB), and 25 single-base substitution (SBS) mutational signatures with VTE. In multivariable Cox regressions adjusted for age, sex, and genetic ancestry, somatic mutations in 4 genes associated with higher rates of VTE at a false-discovery rate of <0.1: CDKN2A (hazard ratio [HR], 1.62; 95% CI, 1.23-2.13), KRAS (HR, 1.31; 95% CI, 1.12-1.53), PCDH15 (HR, 1.48; 95% CI, 1.24-1.76), and TP53 (HR, 1.55; 95% CI, 1.38-1.73). TMB of ≥20 mutations/Mb and 2 DNA mismatch repair signatures (SBS6 and SBS26) associated with lower rates of VTE. Evidence for these associations remained robust after additional adjustment for tumor type, stage, and systemic anticancer treatment. Assessment of interactions between somatic mutations and germline genetic risks for VTE demonstrated that heterozygous carriers of factor V Leiden (rs6025) with somatic PCDH15 mutations had a 6-month VTE incidence of 13% (95% CI, 6%-19%) compared with 4% (95% CI, 3%-5%) in rs6025 carriers without PCDH15 mutations. These findings support the hypothesis that tumor somatic mutations influence risk of VTE. This may provide insights into the pathophysiology of cancer-associated thrombosis and inform future efforts to improve clinical risk prediction.