Abstract 5224: Genome-wide interaction study of smoking and bladder cancer risk: results from the COBLAnCE cohort

Introduction: Bladder Cancer (BC) is the 6th most common cancer and the 9th leading cause of cancer death among men worldwide. Tobacco smoking is the main risk factor for BC. Accumulating evidence has found that genetic variants are also associated with the risk of BC. More insights into the biological mechanism of the disease have been gained through candidate gene-environment interaction studies, with the most known examples of the interactions between cigarette smoking and NAT2 and 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), while focusing on three important smoking behavior characteristics. Materials and Methods: The COBLAnCE cohort comprises 1,800 BC patients included within 14 centers in France between 2012 and 2018. Peripheral blood samples and complete history of tobacco smoking were collected at enrollment and genotyping was performed using the Illumina Global Screening Array with a Multi-Disease drop-in panel. After the quality control and imputation, 9,719,614 Single Nucleotide Polymorphisms (SNPs) were investigated. Genotyping data of 1,674, 1,283 and 1,342 patients were analyzed for smoking status, average tobacco consumption and age at smoking initiation, respectively. Genome-wide association study (GWAS) was conducted using logistic (for smoking status) and linear (for age at smoking initiation and average tobacco consumption, both log-transformed) regression models with each of the imputed SNPs as the independent variable adjusting for gender, age and first ten genetic principal components. Results: For smoking status, none of the SNPs reached the GWAS significant threshold of 5e-08, but results are suggesting tentative loci at 1p31.3 (rs114073636: OR [95%CI] = 0.31 [0.20-0.47], p = 8.68e-08; rs116571608: OR = 0.31 [0.20-0.47], p = 8.87e-08) and 4q22.1 (rs542541627: OR = 1.69 [1.39-2.06], p = 1.81e-07; rs1533294: OR = 1.63 [1.34-1.98], p = 1.01e-06). Analyses of age at smoking initiation revealed three significant SNPs: rs531756449, rs77186197 and rs78947799 with positive interaction associations (β (SE) = 0.3 (0.05), p = 8.26e-09; β = 0.29 (0.05), p = 3.74e-09; β = 0.31 (0.06), p = 3.97e-08, respectively). Only one SNP at 11q24.1, reached the significant threshold for the average tobacco consumption analyses: rs2714069 (β = 0.63 (0.11), p = 1.35e-08). The locus 16p13.3 seems to have protective variants for the interaction with average tobacco consumption: rs113683380 (β = -0.66 (0.12), p = 6.44e-08) and rs113590624 (β = -0.64 (0.12), p = 2.74e-07). Conclusion: Our study suggests new candidate loci interacting with smoking behavior for the risk of BC. Based on a case-only approach, our results need to be validated in a case-control or cohort study. A large-scale meta-analysis GWAS would be needed to identify SNPs with small Minor Allele Frequencies. Citation Format: Maryam Karimi, Sebastian Mendez-Pineda, Hélène Blanché, Anne Boland, Jean-François Deleuze, Xiang-Yu Meng, Karine Groussard, Thierry Lebret, Julia Bonastre, Yves Allory, François Radvanyi, Simone Benhamou, Stefan Michiels. Genome-wide interaction study of smoking and bladder cancer risk: results from the COBLAnCE cohort. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5224.