Genome-Wide Analysis of Structural Variation and Hormone-Related Cancers

Abstract

Hormone-related cancers (HRCs) include some of the most heritable cancer types. Previous studies have identified shared genetic risk factors across HRCs, but work remains to fully map their shared genetic architecture. Although structural variants (SVs) account for a large proportion of genetic variation and have been linked to altered HRC risk in family-based studies, genome-wide evaluation of SVs remains limited. This project utilized data from the All of Us cohort to identify SVs and genomic loci associated with altered HRC risk and characterize structural variation in known HRC-associated regions. We included 68,062 participants, 5,953 of whom had been diagnosed with at least one HRC, in our study. SVs from All of Us were called from short-read whole-genome sequencing data. We performed single variant and region-based association tests using a whole genome logistic regression model that accounted for population structure and relatedness. Analysis did not identify any SVs or genomic regions significantly associated with HRC risk after Bonferroni correction; however, several top-ranked SVs were located near or in regions that may be involved in regulating disease-relevant genes. These findings underscore the importance of SVs in HRC susceptibility and support further investigation of their contribution to inherited cancer risk.