Association between tumour somatic mutations and venous thromboembolism in the 100,000 Genomes Project cancer cohort: a study protocol.

Venous thromboembolism (VTE) is a common cause of morbidity and mortality in patients with cancer. There is evidence that specific aberrations in tumour biology contribute to the pathophysiology of this condition. We plan to examine the association between tumour somatic mutations and VTE in an existing cohort of patients with cancer, who were enrolled to the flagship Genomics England 100,000 Genomes Project. Here, we outline an a-priori analysis plan to address this objective, including details on study cohort selection, exposure and outcome definitions, annotation of genetic variants and planned statistical analyses. We will assess the effect of 1) deleterious somatic DNA variants in each gene; 2) tumour mutational burden and 3) tumour mutational signatures on the rate of VTE (outcome) in a pan-cancer cohort. Sensitivity analyses will be performed to examine the robustness of any associations, including adjustment for potentially correlated co-variates: tumour type, stage and systemic anti-cancer therapy. We hope that results from this study may help to identify key genes which are implicated in the development of cancer associated thrombosis, which may shed light on related mechanistic pathways and/or provide data which can be integrated into genetic risk prediction models for these patients.