Germline structural variation involving gynecologic and breast cancers reveals polygenic signatures of tumor mutational load

Germline structural variants (SVs), genomic variants involving larger segments of the human genome, are understudied in the context of cancer. The impact of germline variants on the regulation of specific genes is highly dependent on tissue and cellular context, necessitating focused, multi-omics studies by cancer tissue of origin. Here, we combine patient germline SV data with tumor multi-omics profiling across 2006 breast and gynecologic cancers, including breast, cervical, ovarian, uterine endometrial, and uterine carcinosarcoma tumors, to determine the extent to which germline SV patterns influence the tumor molecular landscape. Rare germline SV events predicted to disrupt specific cancer-relevant genes cumulatively affect approximately 29% of patients. We find thousands of genes exhibit significant associations between nearby germline SV breakpoints and altered tumor gene expression or DNA methylation. These associations are either specific to tumor type or shared across multiple tumor types and involve numerous cancer-relevant genes. We also identify widespread associations of germline SV patterns with tumor somatic mutational load, including copy number alteration and somatic structural variation, with similar patterns observed in additional cancer cohorts beyond gynecologic and breast cancers. Notably, we find a germline deletion SV spanning UGT2B17 (involving 36% of patients), is associated with reduced UGT2B17 expression and lower tumor mutational load. Germline SV-associated dysregulation in known cancer susceptibility genes or established cancer related genes considerably expands the spectrum of patients with evidence of a germline contribution to cancer development or progression. The patient’s genetic background may influence tumor characteristics, including somatic mutational load.