Loss of function germline mutations in RAD51D in women with ovarian carcinoma

Abstract

Objective: RAD51D, a gene in the Fanconi Anemia-BRCA homologous recombination pathway, has recently been shown to harbor germline mutations responsible for ovarian carcinoma in multiply affected families. We aimed to extend these results to ovarian carcinoma in the general population.

Methods: We sequenced RAD51D in germline DNA from 360 individuals with primary ovarian, peritoneal or fallopian tube carcinoma who were not selected for age of cancer onset or family history. We also sequenced RAD51D in 459 probands from 226 high risk breast cancer families who were wild type for 21 breast and ovarian cancer genes.

Results: Of 360 cases, three (0.8%) carried loss-of-function mutations in RAD51D. All three subjects had ovarian carcinoma; one was also diagnosed with a synchronous endometrial carcinoma. Only one of the three subjects had a family history of breast or ovarian cancer. Combined with previous data for this series, 23.9% of women with unselected ovarian, fallopian tube, or peritoneal carcinoma carried a germline loss-of-function mutation in any of 13 tumor suppressor genes. Among the 449 women and 10 men with familial breast cancer, none carried a loss of function mutation in RAD51D.

Conclusions: These data support the previous observation that loss-of-function mutations in RAD51D predispose to ovarian carcinoma but not to breast carcinoma. We conclude that inherited ovarian cancer is highly heterogeneous genetically, and that approximately one in four ovarian carcinoma patients carry a germline mutation in a known tumor suppressor gene that confers high risk.

Figure 1. Trace Sequences

DNA sequence traces of paired germline and neoplastic DNA from cases with deleterious RAD51D mutations. Retention of heterozygosity at the mutation site is evident in the carcinomas from CF684.01 and 820.01, but the carcinoma from CF 1898.01 has loss of the wildtype allele. The sequence of the mutant transcript (cDNA) sequence for the splice-site mutation revealed skipping of exon 2 leading to a premature stop.

Figure 2. Age Distribution of Germline Mutations in Ovarian Cancer Genes

Proportion of subjects with ovarian, fallopian tube, or peritoneal carcinoma with a loss-of-function germline mutation in RAD51D, BRCA1, BRCA2, BARD1, BRIP1, CHEK2, MRE11A, MSH6, NBN, PALB2, RAD50, RAD51C, or TP53 (see also Walsh et al. 2011).