Elsevier

Gynecologic Oncology

Volume 119, Issue 1, October 2010, Pages 131-135
Gynecologic Oncology

Identification of point mutations and large rearrangements in the BRCA1 gene in 667 Turkish unselected ovarian cancer patients

https://doi.org/10.1016/j.ygyno.2010.05.018Get rights and content

Abstract

Objective

The aim of this study was to evaluate the prevalence and spectrum of a known founder mutation, 5382insC and large genomic rearrangements (LGRs) in BRCA1 in ovarian cancer patients in Turkey. The additional aim was to determine the genetic testing strategy in Turkish breast/ovarian cancer family.

Methods

Six hundred and sixty-seven ovarian cancer patients from five large geographical regions in Turkey, 61 of which had family history of breast/ovarian cancer, were tested for the mutation 5382insC by mutagenically separated polymerase chain reaction and direct sequencing of the entire coding sequence and the splicing sites. Additionally, multiplex ligation-dependent probe amplification (MLPA) was performed for large mutational scanning of BRCA1 gene in unselected ovarian cancer.

Results

In this study, BRCA1 point mutations were observed in 1% of all patients and 9.8% of familial cases: 5382insC, unique novel missense variant-G1748S and unclassified splice site variant IVS20 + 5A > T. 5382insC was observed in two patients. However, G1748S, previously unreported, was found in four patients and thus led to the conclusion that this mutation may be unique to Turkey. A splice site variant, IVS20 + 5A > T, was detected in three patients, with two of them including G1748S and IVS20 + 5A > T, together. Using MLPA, six different distinct LGRs in BRCA1 were observed: the deletion of E1A-1B-2, E11, E17-19, E18 and E18-19 and duplication of E5-9. The prevalence of LGRs in this study was 40.9% among patients with family history. The deletion of E1A-1B-2 was the common mutation, and patients with this deletion were referred to us from four different geographical regions in Turkey. Therefore, it was hypothesized that this deletion covering E1-2 is common in Turkey.

Conclusion

LGRs in BRCA1 were strongly associated with positive family history among the Turkish population. On the basis of these findings, it can be recommended that a low-cost screening for LGRs in BRCA1 may be the first-line mutation detection method in families with strong breast/ovarian cancer history in Turkey.

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.

Section snippets

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.

References (27)

  • T.O. Hansen et al.

    Large BRCA1 and BRCA2 genomic rearrangements in Danish high risk breast-ovarian cancer families

    Breast Cancer Res Treat

    (2009)
  • S. Palanca Suela et al.

    Group for Assessment of Hereditary Cancer of Valencia Community. Identification of a novel BRCA1 large genomic rearrangement in a Spanish breast/ovarian cancer family

    Breast Cancer Res Treat

    (2008)
  • M. Ratajska et al.

    BRCA1 and BRCA2 point mutations and large rearrangements in breast and ovarian cancer families in Northern Poland

    Oncol Rep

    (2008)
  • View full text