Analysis of RAD51D in ovarian cancer patients and families with a history of ovarian or breast cancer.

Ella R Thompson,Kconfab Kconfab,Paul A James,Sarah Sawyer,Simone M Rowley,Gillian Mitchell,Ian G Campbell,Alison H Trainer,Diana M Eccles,Nathan A Ellis

doi:10.1371/journal.pone.0054772

Abstract

Mutations in RAD51D have been associated with an increased risk of hereditary ovarian cancer and although they have been observed in the context of breast and ovarian cancer families, the association with breast cancer is unclear. The aim of this current study was to validate the reported association of RAD51D with ovarian cancer and assess for an association with breast cancer. We screened for RAD51D mutations in BRCA1/2 mutation-negative index cases from 1,060 familial breast and/or ovarian cancer families (including 741 affected by breast cancer only) and in 245 unselected ovarian cancer cases. Exons containing novel non-synonymous variants were screened in 466 controls. Two overtly deleterious RAD51D mutations were identified among the unselected ovarian cancers cases (0.82%) but none were detected among the 1,060 families. Our data provide additional evidence that RAD51D mutations are enriched among ovarian cancer patients, but are extremely rare among familial breast cancer patients.

Highlights

RAD51 homolog D (S. cerevisiae) (RAD51D/RAD51L3; MIM#602954) is a component of the homologous recombination DNA repair pathway
RAD51D has subsequently been investigated in an additional series of 175 breast and ovarian cancer families, with an additional mutation being identified among the 51 families with at least two ovarian cancers [4]
The familial cohort included 540 individuals with verified personal and family histories of breast and/or ovarian cancer who were previously assessed at the Peter MacCallum Cancer Centre Familial Cancer Centre (Australia), as well as index cases from 520 multiple case breast cancer families obtained from the Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer [11]. kConFab families are recruited through Familial Cancer Centres throughout Australia and New Zealand

Summary

Introduction

RAD51 homolog D (S. cerevisiae) (RAD51D/RAD51L3; MIM#602954) is a component of the homologous recombination DNA repair pathway. Loveday et al [3] recently reported the identification of eight truncating mutations in RAD51D among 911 families with histories of breast and ovarian cancer, compared to one mutation among 1,060 population controls. They reported a significantly elevated risk of ovarian cancer (6.30, 95% CI 2.86–13.85) but did not detect a significantly elevated risk of breast cancer (1.32, 95% CI 0.59–2.96). RAD51D has subsequently been investigated in an additional series of 175 breast and ovarian cancer families, with an additional mutation being identified among the 51 families with at least two ovarian cancers (and among the 75 probands affected by ovarian cancer) [4]. Pelttari et al screened for the c.576+1G variant in an additional 2,200 breast and 553 ovarian cancer patients and overall identified 5/707 patients with a personal or family history of ovarian cancer compared to 2/2,105 breast cancer only patients/families

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Results