Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.

Epithelial ovarian cancer (EOC) is a heterogeneous disease with a major heritable component. The different histotypes of invasive disease - high grade serous, clear cell, endometrioid and mucinous - are associated with different underlying genetic susceptibility and epidemiological and lifestyle risk factors, all of which contribute to the different biology and clinical characteristics of each histotype. A combination of familial and population based sequencing studies, and genome wide association studies (GWAS) have identified a range of genetic susceptibility alleles for EOC comprising rare but highly penetrant genes (e.g. BRCA1, BRCA2) that are responsible for familial clustering of ovarian cancer cases; more moderate penetrance susceptibility genes (e.g. BRIP1, RAD51C/D, MSH6); and multiple common but low penetrance susceptibility alleles identified by GWAS. Identifying genetic risk alleles for ovarian cancer has had a significant impact on disease prevention strategies; for example it is now routine clinical practice for individuals with germline BRCA1 and BRCA2 mutations to undergo risk reducing salpingo-oophorectomy. Because ovarian cancers are commonly diagnosed at a late clinical stage when the prognosis is poor, the continued development of genetic risk prediction and prevention strategies will represent an important approach to reduce mortality due to ovarian cancer. Advances in genomics technologies that enable more high-throughput genetic testing, combined with research studies that identify additional EOC risk alleles will likely provide further opportunities to establish polygenic risk prediction approaches, based on combinations of rare high/moderate penetrance susceptibility genes and common, low penetrance susceptibility alleles. This article reviews the current literature describing the genetic and epidemiological components of ovarian cancer risk, and discusses both the opportunities and challenges in using this information for clinical risk prediction and prevention.

The functional consequences of somatic non-coding mutations in ovarian cancer (OC) are unknown. To identify regulatory elements (RE) and genes perturbed by acquired non-coding variants, here we establish epigenomic and transcriptomic landscapes of primary OCs using H3K27ac ChIP-seq and RNA-seq, and then integrate these with whole genome sequencing data from 232 OCs. We identify 25 frequently mutated regulatory elements, including an enhancer at 6p22.1 which associates with differential expression of ZSCAN16 (P = 6.6 × 10-4) and ZSCAN12 (P = 0.02). CRISPR/Cas9 knockout of this enhancer induces downregulation of both genes. Globally, there is an enrichment of single nucleotide variants in active binding sites for TEAD4 (P = 6 × 10-11) and its binding partner PAX8 (P = 2×10-10), a known lineage-specific transcription factor in OC. In addition, the collection ofcisREs associated with PAX8 comprise the most frequently mutated set of enhancers in OC (P = 0.003). These data indicate that non-coding somatic mutations disrupt the PAX8 transcriptional network during OC development.