Clinical Characteristics of Ovarian Cancer Classified by BRCA1, BRCA2 and RAD51C Status

Abstract

We evaluated homologous recombination deficient (HRD) phenotypes in epithelial ovarian cancer (EOC) considering BRCA1, BRCA2, and RAD51C in a large well-annotated patient set. We evaluated EOC patients for germline deleterious mutations (n = 899), somatic mutations (n = 279) and epigenetic alterations (n = 482) in these genes using NGS and genome-wide methylation arrays. Deleterious germline mutations were identified in 32 (3.6%) patients for BRCA1, in 28 (3.1%) for BRCA2 and in 26 (2.9%) for RAD51C. Ten somatically sequenced patients had deleterious alterations, six (2.1%) in BRCA1 and four (1.4%) in BRCA2. Fifty two patients (10.8%) had methylated BRCA1 or RAD51C. HRD patients with germline or somatic alterations in any gene were more likely to be high grade serous, have an earlier diagnosis age and have ovarian and/or breast cancer family history. The HRD phenotype was most common in high grade serous EOC. Identification of EOC patients with an HRD phenotype may help tailor specific therapies.

Genetic testing for RAD51C mutations: in the clinic and community

“…All rights reserved (table 2). All in all, 32 mutations were identified among 1,798 unselected ovarian cancer cases, with an overall prevalence of 1.8% (table 1) [16,17,22,24]. Excluding the study by Cunningham et al (2014), the prevalence in unselected ovarian cancer cases is about 0.7%.…”

“…In three of the studies, the carrier frequencies ranged from 0.4-1.1% [17,22,24]. Cunningham [16]. However, they included two common missense variants, p.Gly264Ser and p.Thr287Ala, which have been identified in virtually all studies, and are generally considered to be benign based on their prevalence in healthy control populations This article is protected by copyright.…”

“…This mutation was identified recently in the USA [16]; however, details on the ethnicity of carriers were not provided. The presence of the same c.774delT mutation identified in Swedish cases from three separate studies (average prevalence 0.6%), suggests that it might be a recurrent mutation and should be studied further in the Swedish population.…”

“…Several studies from various countries and ethnic groups have attempted to confirm these findings. Eleven studies have reported mutations with varying frequencies (0.4 -2.9%; summarized in table 1) [13][14][15][16][17][18][19][20][21][22][23][24], but eight studies failed to detect any clearly pathogenic mutation [25][26][27][28][29][30][31]. Of all families with an identified mutation in the 11 studies, only one mutation was found in a family without ovarian cancer (prevalence 0.2%) [18,21].…”

Relationship between RAS Association Domain Family Protein 1A Promoter Methylation and the Clinicopathological Characteristics in Patients with Ovarian Cancer: A Systematic Meta-Analysis

“…As a frequent epigenetic alteration, DNA methylation plays a key role in the carcinogenesis and progression of various human cancers [6-9]. Some aberrantly methylated genes have been found to be linked to the development, progression, and prognosis of ovarian carcinoma [10-12]. As a common isoform of the Ras-association domain family 1 ( RASSF1 ), RAS association domain family protein 1A ( RASSF1A ), a key tumor suppressor gene (TSG), is mapped to human chromosomal region 3p21.3 [13, 14].…”