Whole‐exome sequencing of ovarian cancer families uncovers putative predisposition genes

Abstract

Despite the identification of several ovarian cancer (OC) predisposition genes, a large proportion of familial OC risk remains unexplained. We adopted a two‐stage design to identify new OC predisposition genes. We first carried out a large germline whole‐exome sequencing study on 158 patients from 140 families with significant OC history, but without evidence of genetic predisposition due to BRCA1/2. We then evaluated the potential candidate genes in a large case–control association study involving 381 OC cases in the Cancer Genome Atlas project and 27,173 population controls from the Exome Aggregation Consortium. Two new putative OC risk genes were identified, namely, ANKRD11, a putative tumor suppressor, and POLE, an enzyme involved in DNA repair and replication. These two genes likely confer moderate OC risk. We performed in vitro experiments and showed an ANKRD11 mutation identified in our patients markedly lowered the protein expression by compromising protein stability. Upon future validation and functional characterization, these genes may shed light on cancer etiology along with improving ascertainment power and preventive care of individuals at high risk of OC.

Exome sequencing of familial high-grade serous ovarian carcinoma reveals heterogeneity for rare candidate susceptibility genes

“…Similarly, Lu et al 20 interrogated WES data from Ambry Genetics for 2051 women with ovarian carcinoma for only a small number of known 'cancer-associated' genes, and demonstrated significant enrichment for variants in six genes (ATM, CHEK2, MSH6, PALB2, RAD51C and TP53). Recently, Zhu et al 21 analysed WES data from 158 BRCA1 and BRCA2-negative ovarian carcinoma cases and identified ANKRD11 and POLE as putative risk genes following validation studies. Neither gene was found to be enriched for LoF variants in our cohort.…”

“…Efforts to identify additional moderate-to-high-risk hereditary breast and ovarian cancer (HBOC) genes have largely been restricted to candidate gene approaches using targeted nextgeneration sequencing (NGS) panels of known cancer predisposition genes [12][13][14][15][16][17][18] , which have collectively only resolved a very small proportion of unexplained families. Although three studies utilised data from whole-exome sequencing (WES) of BRCA1 and BRCA2-negative ovarian carcinoma patients [19][20][21] , these analysed only a subset of candidate genes in the available data and included non-HGSOC tumour types in their case cohorts. Others utilised germline sequencing data from The Cancer Genome Atlas (TCGA) [22][23][24][25] , but this approach is limited by the diverse technologies used to generate TCGA data along with the absence of any linked family history information.…”

An Overview of Candidate Therapeutic Target Genes in Ovarian Cancer

“…Although ERCC2 has been correlated with a more aggressive phenotype in head and neck tumors, the role of both proteins in OC is still unclear [ 114 ]. A higher somatic mutation burden has been recently reported in OC for the POLE gene, encoding for an enzyme involved in the DNA repair and replication; the impact of POLE mutations also seems to be more prominent in sporadic OC than in familiar one [ 115 ]. Upregulation of the RPA3 gene has been associated with HGSOC proliferation [ 116 ].…”

Peripheral bloodBRCA1methylation profiling to predict familial ovarian cancer

“…Recent work found that two genes— AKRD11 , a putative tumor suppressor, and POLE , a DNA repair and replication enzyme—predispose the development of ovarian cancer. Despite ongoing research to identify predisposing genes, a proportion of ovarian cancer risk cannot yet be fully explained [ 6 ].…”