Identification of point mutations and large rearrangements in the BRCA1 gene in 667 Turkish unselected ovarian cancer patients
Introduction
Epithelial ovarian cancers are the hallmark of hereditary cancer syndromes which are related to cancer predisposing mutations in BRCA1 (MIM# 113705) and BRCA2 (MIM# 600185) genes. BRCA1 and BRCA2 are tumor-suppressor genes involved in DNA repair, cell cycle regulation and genomic integrity control [1]. Approximately 10% of all epithelial ovarian cancers are attributable to an inherited susceptibility [2]. The risk for ovarian cancer is dependent whether the mutation has occurred in BRCA1 or BRCA2, with estimated risks ranging from 36% to 46% in BRCA1 mutation carriers and from 10% to 27% in BRCA2 mutation carriers [3].
Germ-line mutations in the BRCA1 and BRCA2 genes have been identified frequently and some have been identified as founder mutations among different populations. The genetic transmission pattern is dominant inheritance with an approximate incidence of 1/800 in Caucasians and 1/50 in Ashkenazi Jews. These mutations have been found to be related to hereditary breast and ovarian cancer but also to prostate cancer, colon cancer, pancreatic cancer and male breast cancer [4].
Point mutations are spread throughout the whole coding sequence of both BRCA1 and BRCA2 genes (Breast Cancer Information Core, BIC, http://nchgr.nih.gov/Intramural.research/Lab_ transfer/Bic/). However, the percentage of germ-line mutations in these genes is lower than expected according to the estimates of genetic linkage analysis. This relatively low estimate can partly be explained by the BRCA genes alterations that escape to the most common methods for point mutation detection [5]. In the BRCA1 gene, such mutations are more frequently represented by large deletions and duplications that disrupt one or more exons, causing synthesis of aberrant proteins. Over the past 10 years, several of these rearrangements have been identified and have been shown to be related to a population specific proportion of the BRCA mutational spectrum [6], [7], [8], [9].
The incidence of ovarian carcinoma is 6.3 per 100.000, and approximately 1054 new cases of epithelial ovarian carcinoma are diagnosed annually in Turkey (Turkish Ministry of Health, Cancer Control Department, www.kanser.gov.tr). A known founder mutation, 5382insC, has previously been identified in Turkish breast and ovarian cancer patients [10], [11], [12], [13], [14], [15], resulting in this large-scale mutational analysis in Turkey. Additionally, large genomic rearrangements in BRCA1 were also screened for the first time in ovarian cancer patients in Turkey.
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Patients and methods
During the period 1999–2009, successions of 667 consecutive patients with unselected ovarian cancer were determined. The contributing centers were Hacettepe University Department of Genetics, Department of Gynecology-Obstetrics and Etlik Zübeyde Hanım Women's Health Training and Research Hospital, Department of Gynecologic Oncology, in Ankara. These centers are reference hospitals, and the samples were representative of the major geographical areas of Anatolia, including Central and Eastern
Results
Six hundred and sixty-seven women were identified through the cancer registry. Of these women, 9.1% (61/667) had positive family history of beast and/or ovarian cancer in close relatives. Nine of 61 familial cancers had no breast cancer and these were diagnosed as site-specific ovarian cancer families. The average age at diagnosis among patients with BRCA1 mutations was 50.4 years (Table 1), and the age at diagnosis of the women with no mutation was 53.3 years.
The histopathology of tumors was
Discussion
Our study on 667 unselected cases of ovarian cancer is the largest series to date in Turkey and is comprehensively representative of all incident ovarian cancer, arising in the major geographic area of Anatolia. According to age at diagnosis, BRCA1 mutations were observed in women ∼ 3 years earlier than those among women not found to have mutations. Previously, it has been demonstrated that BRCA1-associated cases typically occur during patients' 40s and 50s, and only a small percentage of cases
Acknowledgments
This study was supported by grants from the State Planning Organization of Turkey (Project 9901042) and the Hacettepe University (Project 07A101001). We also thank all patients for participation in this study.
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