Tumor Whole-Genome Sequencing for Prediction of Venous Thromboembolism in Patients With Metastasized Solid Cancer

Background: International guidelines suggest prophylactic anticoagulation for patients with cancer at high risk of venous thromboembolism (VTE). Here, we evaluated whether tumor whole-genome sequencing data may improve the selection of high-risk patients. Methods: In a pan-cancer cohort of 3087 patients, associations of candidate clinical predictors, the germline extended 297-single nucleotide polymorphism polygenic risk score, tumor mutational characteristics, and somatic tumor mutations with VTE were estimated by calculating hazard ratios (HRs). Results: During 12-month follow-up, 237 (7.7%) developed VTE. The germline extended 297-single nucleotide polymorphism score was associated with VTE (HR per point increase, 2.11 95% CI, 1.45–3.06), as well as the total number of somatic structural variants (HR per 1000 increase, 1.21 95% CI, 1.07–1.37) and 129 somatic mutations (unadjusted P <0.05), including POLR2E (HR, 3.34 95% CI, 1.68–6.97), PALM (HR, 3.73 95% CI, 1.74–7.99), TBX22 (HR, 2.47 95% CI, 1.40–4.35), and ELANE (HR, 3.22 95% CI, 1.51–6.87). To further explore the potential of tumor whole-genome sequencing, prediction models were constructed including selected clinical predictors only (model 1), clinical predictors and germline variants (model 2), and the combination of clinical predictors, germline variants, and 14 top discriminating somatic mutations (model 3). The optimism corrected concordance index was 0.66 (95% CI, 0.62–0.69) for model 1, 0.67 (95% CI, 0.62–0.72) for model 2, and 0.77 (95% CI, 0.72–0.81) for model 3. This was significantly higher than that of the currently endorsed clinical Khorana VTE risk score (concordance index, 0.55 95% CI, 0.51–0.59; P <0.005). Conclusions: These data indicate that tumor whole-genome sequencing may improve VTE prediction by clinical risk scores. Validation studies to confirm these findings are needed.