Genomic Profiling Identifies Somatic Mutations Predicting Thromboembolic Risk in Patients with Solid Tumors

Cancer-associated venous thromboembolism (CAT) is a well-described complication of cancer and a leading cause of death in cancer patients. The purpose of this study was to assess potential associations of molecular signatures with CAT, including tumor-specific mutations and the presence of clonal hematopoiesis. We analyzed deep-coverage targeted DNA-sequencing data of >14,000 solid tumor samples using the MSK-IMPACT platform to identify somatic alterations associated with VTE. Endpoint was defined as the first instance of cancer-associated pulmonary embolism and/or proximal/distal lower extremity deep vein thrombosis. Cause-specific Cox proportional hazards regression was used, adjusting for pertinent clinical covariates. Of 11,695 evaluable individuals, 72% had metastatic disease at time of IMPACT. Tumor-specific mutations in KRAS (HR=1.34 [1.09-1.64]; adjusted p=0.08), STK11 (HR=2.12 [1.55-2.89]; adjusted p<0.001), KEAP1 (HR=1.84 [1.21-2.79]; adjusted p=0.07), CTNNB1 (HR=1.73 [1.15-2.60]; adjusted p=0.09), CDKN2B (HR= 1.45 [1.13-1.85], adjusted p=0.07) and MET (HR=1.83 [1.15-2.92]; adjusted p=0.09) were associated with a significantly increased risk of CAT independent of tumor type. Mutations in SETD2 were associated with a decreased risk of CAT (HR=0.35 [0.16-0.79], adjusted p=0.09). The presence of clonal hematopoiesis was not associated with an increased VTE rate. This is the first large-scale analysis to elucidate tumor-specific genomic events associated with CAT. Somatic tumor mutations of STK11, KRAS, CTNNB1, KEAP1, CDKN2B and MET were associated with an increased risk of VTE in solid tumor patients. Further analysis is needed to validate these findings and identify additional molecular signatures unique to individual tumor types. Key PointsO_LITumor mutations in STK11, KRAS, CTNNB1, KEAP1, CDKN2B, MET and SETD2 modulate the risk of cancer-associated thrombosis. C_LIO_LIThe presence of clonal hematopoiesis does not affect the risk of cancer-associated thrombosis. C_LI