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. 2017 Jun 7;12(6):e0178450.
doi: 10.1371/journal.pone.0178450. eCollection 2017.

Reanalysis of BRCA1/2 negative high risk ovarian cancer patients reveals novel germline risk loci and insights into missing heritability

Jaime L Stafford  1 , Gregory Dyson  2 , Nancy K Levin  2 , Sophia Chaudhry  1 , Rita Rosati  2 , Hasini Kalpage  1 , Courtney Wernette  1 , Nancie Petrucelli  2 , Michael S Simon  2 , Michael A Tainsky  1   2   3
Affiliations

Reanalysis of BRCA1/2 negative high risk ovarian cancer patients reveals novel germline risk loci and insights into missing heritability

Jaime L Stafford et al. PLoS One. .

Abstract

While up to 25% of ovarian cancer (OVCA) cases are thought to be due to inherited factors, the majority of genetic risk remains unexplained. To address this gap, we sought to identify previously undescribed OVCA risk variants through the whole exome sequencing (WES) and candidate gene analysis of 48 women with ovarian cancer and selected for high risk of genetic inheritance, yet negative for any known pathogenic variants in either BRCA1 or BRCA2. In silico SNP analysis was employed to identify suspect variants followed by validation using Sanger DNA sequencing. We identified five pathogenic variants in our sample, four of which are in two genes featured on current multi-gene panels; (RAD51D, ATM). In addition, we found a pathogenic FANCM variant (R1931*) which has been recently implicated in familial breast cancer risk. Numerous rare and predicted to be damaging variants of unknown significance were detected in genes on current commercial testing panels, most prominently in ATM (n = 6) and PALB2 (n = 5). The BRCA2 variant p.K3326*, resulting in a 93 amino acid truncation, was overrepresented in our sample (odds ratio = 4.95, p = 0.01) and coexisted in the germline of these women with other deleterious variants, suggesting a possible role as a modifier of genetic penetrance. Furthermore, we detected loss of function variants in non-panel genes involved in OVCA relevant pathways; DNA repair and cell cycle control, including CHEK1, TP53I3, REC8, HMMR, RAD52, RAD1, POLK, POLQ, and MCM4. In summary, our study implicates novel risk loci as well as highlights the clinical utility for retesting BRCA1/2 negative OVCA patients by genomic sequencing and analysis of genes in relevant pathways.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Summary of variant findings amongst our 48 subjects of high risk for genetic inheritance of OVCA.
Ten percent of subjects were found to harbor a clear pathogenic variant, while 37% harbored a variant of unknown clinical significance (VUS) in a gene featured on current HBOC testing panels. 52% of subjects were found to be negative for either a clear pathogenic variant or a VUS in a known breast or ovarian cancer predisposing gene.
Fig 2
Fig 2. OCF28 kindred.
Arrow indicates patient OCF28-1.
See this image and copyright information in PMC

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