A Case-Only Genome-Wide Interaction Study of Smoking and Bladder Cancer Risk: Results from the COBLAnCE Cohort

SIMPLE SUMMARY: Bladder cancer is one of the most common cancers worldwide. The most important known cause of bladder cancer is tobacco smoking. Several genetic variations are also linked to the risk of developing bladder cancer. In this study, we focused on how smoking behavior interacts with genes to affect bladder cancer risk using the French national prospective COBLAnCE cohort (COhort to study BLAdder CancEr). The COBLAnCE cohort comprises approximately 1700 bladder cancer patients with available smoking and genetic information. We identified new chromosomal regions (specifically, genes located at 4q22.1, 12p13.1, and 16p13.3) of which variations may interact with smoking behavior in relation to bladder cancer risk. These findings need to be replicated in other studies. ABSTRACT: Bladder cancer (BC) is the 6th most common cancer worldwide, with tobacco smoking considered as its main risk factor. Accumulating evidence has found associations between genetic variants and the risk of BC. Candidate gene-environment interaction studies have suggested interactions between cigarette smoking and NAT2/GSTM1 gene variants. Our objective was to perform a genome-wide association case-only study using the French national prospective COBLAnCE cohort (COhort to study BLAdder CancEr), focusing on smoking behavior. The COBLAnCE cohort comprises 1800 BC patients enrolled between 2012 and 2018. Peripheral blood samples collected at enrolment were genotyped using the Illumina Global Screening Array with a Multi-Disease drop-in panel. Genotyping data (9,719,614 single nucleotide polymorphisms (SNP)) of 1674, 1283, and 1342 patients were analyzed for smoking status, average tobacco consumption, and age at smoking initiation, respectively. A genome-wide association study (GWAS) was conducted adjusting for gender, age, and genetic principal components. The results suggest new candidate loci (4q22.1, 12p13.1, 16p13.3) interacting with smoking behavior for the risk of BC. Our results need to be validated in other case-control or cohort studies.