BRCA2 pathogenic variants (PVs) were associated with increased risk of cancers in non-reproductive tissues, suggesting that additional pathways and mechanisms besides those related with sexual hormonal environment may explain the heterogenous cancer spectrum associated with BRCA2 PVs [1]. BRCA2 PVs may result in mutated proteins with defected capabilities to interact with environmental carcinogens and inflammation, modifying cancer risks in specific tissues. Pancreatic cancer represents the ideal model to further study such interaction, given its established associations with both BRCA2 PVs and environmental and inflammatory risk factors [2].
In this project, we aim to assess whether the pancreatic cancer risk conferred by BRCA2 PVs could be modulated by gene-environment interactions, performing an association analysis between BRCA2 genotypes and environmental/lifestyle exposures.
Whole exome sequencing data together with demographic and exposure data for each pancreatic cancer patient included in UK biobank will be retrieved to identify BRCA2 PVs. Candidate available exposures to be assessed will include sex, age, ethnic group, cigarette smoking status, alcohol intake frequency, work history, residential air pollution, obesity/BMI, history of pancreatitis. Gene-environment interactions will be investigated using a case-only design by logistic regression models for each exposure, with adjustment for age and sex [3]. Cancer and gene specificity of eventual associations will be validated by performing similar analysis on BRCA1 PV carriers and on patients affected by other solid tumors, such as breast cancer.
1. Li S, Silvestri V, et al. Cancer Risks Associated with BRCA1 and BRCA2 Pathogenic Variants. J Clin Oncol 2022
2. Ke TM, et al. Risk Factors Associated with Pancreatic Cancer in the UK Biobank Cohort. Cancers 2022
3. Usui Y, et al. Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. NEJM 2023