Abstract 6147: Genome-wide association study identifies new genetic susceptibility loci for multiple primary cancers

Abstract Objectives: Genetic susceptibility is thought to contribute to the development of multiple primary cancers (MPC), often called secondary cancers. Although rare variants contribute to risk, these only account for a small fraction of MPC cases. The contribution of common variants to risk is unknown. Methods: To identify common genetic variants associated with the risk of MPC, we conducted a trans-ancestry meta-analysis of genome-wide association studies (GWAS), including 7,360 MPC cases and 138,684 controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and UK Biobank (UKBB). Association analyses were performed separately by genetic ancestry, genotype platform, and study, adjusting for age, sex, and principal components, and the results were meta-analyzed together using a fixed effects model. Genome-wide SNP heritability was estimated using GCTA. Pathway and functional enrichment analyses were conducted to gain insights into potential biological mechanisms underlying discovered loci. Results: We identified one novel locus at chromosome 3q26.2 (LRRC34, rs7621631) that was associated with MPC risk (P=1.16x10-8). Variants in this region have been previously associated with telomere length, suggesting a possible underlying mechanism. In sex-stratified analyses, we identified an additional locus at chromosome 12q24.33 (intergenic, rs10466868) associated with MPC in men (P= 7.76x10-8), but not women. Although the risk associated with these two discovered loci was small, the genome-wide SNP heritability was estimated to be 12%, suggesting that there are likely more common variants to be discovered for MPC risk. Conclusions: Our study demonstrates that common genetic variation contributes to the risk of multiple primary cancers and suggests additional loci are likely to be identified with larger studies. Citation Format: Shisi He, James Perry, Shengchao Li, Braxton D. Mitchell, Yuji Zhang, Shuo Chen, Laura Beane-Freeman, Kathryn Hughes Barry, Sonja I. Berndt. Genome-wide association study identifies new genetic susceptibility loci for multiple primary cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6147.