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

## TL;DR

This study aims to find if genetic changes in tumors are linked to blood clots in cancer patients, which could help predict and understand this dangerous condition.

## Contribution

The study introduces a novel analysis of tumor somatic mutations and their association with venous thromboembolism in a large cancer cohort.

## Key findings

- Examines the effect of deleterious somatic DNA variants on venous thromboembolism rates.
- Investigates the role of tumor mutational burden and signatures in cancer-associated blood clots.
- Plans to identify key genes involved in cancer-related thrombosis for potential risk prediction models.

## Abstract

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.

People with cancer have a significantly higher risk of developing a condition known as venous thromboembolism (a type of blood clot). This is a major cause of illness and death. Rates of venous thromboembolism vary between different types of cancer and the reasons for this are not well understood. The purpose of this study is to evaluate whether there is a link between acquired genetic variants (which occur within the tumour) and venous thromboembolism. This study will hopefully contribute to our understanding of the mechanisms which drive the development of cancer-associated venous thromboembolism and help future efforts to develop models for more accurately identifying people at highest risk of the condition.