# Characterizing somatic mutations in ovarian cancer germline risk regions

## TL;DR

This study explores how germline genetic risk regions influence somatic mutations in epithelial ovarian cancer, revealing key patterns and regulatory impacts.

## Contribution

The study integrates germline and somatic mutations with regulatory data to uncover their combined role in ovarian cancer.

## Key findings

- Germline susceptibility genes are associated with key mutational signatures like mismatch repair deficiency.
- Somatic mutations are enriched in active enhancers and promoters within ovarian cancer risk loci.
- Germline and somatic mutations jointly affect transcription factor binding sites in cancer development.

## Abstract

Epithelial ovarian cancer (EOC) genetics research has been focused on germline or somatic mutations independently. Emerging evidence suggests that the somatic mutational landscape can be shaped by the germline genetic background. In this study, we aim to unravel the role of somatic alterations within EOC germline susceptibility regions by incorporating functional annotations. We investigate somatic events, including mutational signatures, point mutations, copy number alterations, and transcription factor binding disruptions, within 33 EOC germline susceptibility regions. Our analysis identifies significant associations between candidate germline susceptibility genes and somatic mutational signatures known to be key risk factors for EOC, such as mismatch repair deficiency, age-related mutagenesis, and homologous recombination deficiency. In addition, we find somatic point mutations and copy number alterations are significantly enriched in histotype-specific active enhancers and promoters within EOC risk loci. Furthermore, we examine the impact of germline variants and somatic mutations on transcription factor binding sites, identifying cancer developmental transcription factor motifs frequently affected by both types of mutations. Overall, our study highlights the importance of integrating germline and somatic mutations with regulatory and epigenomic data to gain insights into the genetic basis of EOC.

Integrating germline and somatic mutations with regulatory data reveals how epithelial ovarian cancer risk regions shape somatic alterations, highlighting key mutational signatures, enhancer disruptions, and transcription factor binding changes.