One in 10 ovarian cancer patients carry germ line BRCA1 or BRCA2 mutations

Abstract

At least 10% of all ovarian cancers are estimated to have a hereditary background. Hereditary breast–ovarian cancer (HBOC) due to mutations in the BRCA genes is a major cause of hereditary ovarian cancer, although its frequency and relationship to age and family history in unselected series of ovarian cancers is not completely known. We report here the results of a full mutational screening analysis for germ line BRCA1 and BRCA2 mutations in 161 patients with invasive epithelial ovarian carcinomas. Age at diagnosis ranged from 22 to 82 years (mean 59 years). Deleterious (frame-shift, nonsense and missense) mutations were detected in 13/161 (8%) of the patients and affected BRCA1 in 12 cases and BRCA2 in one case. Four additional missense variants (one in BRCA1 and three in BRCA2) with a possible association with an increased risk ovarian cancer were revealed, resulting in a total frequency of BRCA gene alterations of 17/161 (11%). The 13 patients with deleterious mutations had a mean age of 57 years (range 41–76 years) and only three of these patients were below 50 years of age. A family history of at least one breast cancer and/or ovarian cancer was reported in all but 1 of the patients with BRCA mutations compared with only 24% of patients without mutations. Our findings in this prospective study confirm approximately 1 in 10 patients with ovarian cancer carry a germ line BRCA gene mutation associated with HBOC, and also indicate that a large number of these patients are over 50 years of age at diagnosis.

Introduction

Ovarian cancer represents the seventh most common cancer in the world 1, 2 with a high incidence being found in Scandinavia, where ovarian cancer affects approximately 2/100 females at a median age of 64 years, with 80% of the patients being above 50 years of age at diagnosis 3, 4. A family history of ovarian cancer is a strong and consistent risk factor for the disease and, consequently, first-degree relatives of patients with ovarian cancer have a 2- to 4-fold increased risk of the disease 5, 6. Familial ovarian cancer is associated with tumour development about 10 years earlier than its sporadic counterpart and may occur in different contexts; site-specific ovarian cancer for which no genetic defect has yet been identified, hereditary breast–ovarian cancer (HBOC), and as part of hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome) 7, 8, 9, 10. Among families in which disease-causing mutations have been detected, HBOC and HNPCC have been estimated to account for 85–90% and 10–15% of cases, respectively 9, 11. Among the HBOC patients, BRCA1 accounts for 70–80% of the mutations and is estimated to confer a 40–60% life-time risk for ovarian cancer at a mean age of 50–55 years, whereas BRCA2 accounts for 10–20% of the mutations identified and yields a 10–20% risk of ovarian cancer at a mean age 55–65 years 7, 12, 13, 14, 15. The BRCA proteins are multifunctional with important control functions in homologous recombination, DNA double-strand break repair and early cellular response to DNA damage. BRCA1 also has a transcriptional activator or repressor function and possesses a central role in chromatin remodelling and centrosome regulation. Hence, BRCA1 and BRCA2 function as tumour suppressors and, presumably, cause tumour development through a caretaker defect with an increased genetic instability due to alterations in chromosome structure [16].

As an extension of a previous retrospective pilot study of 37 invasive epithelial ovarian carcinomas, which indicated a high frequency (16%) of germ line BRCA gene mutations [17] we have screened the BRCA1 and BRCA2 genes for germ line mutations in a prospective series of ovarian cancer patients. Recognition of patients with HBOC among ovarian cancer patients is important in order to suggest adequate treatment and follow-up for the patients and to offer genetic counselling followed by predictive testing and possible risk-reducing prophylactic surgery to relatives at risk.