Germ line BRCA1 and BRCA2 gene mutations in Turkish breast cancer patients
Introduction
Breast cancer is one of the most common malignancies affecting women [1] (http://www.nci.nih.gov/public/factbook98/incidence.htm). Inherited gene mutations may be responsible for 5–10% of breast cancer cases 1, 2, 3. Ovarian cancer is also known to have a familial component [4].
Two genes associated with inherited predisposition to breast and/or ovarian cancer have been identified. These are BRCA1 on chromosome 17q12-21 [1], and BRCA2 on chromosome 13q12-13 [5]. Population genetics studies aimed at determining the relative contributions of these genes in hereditary breast and/or ovarian cancer have shown a wide variation among different populations [6]. For example, in families with three or more cases of female breast and/or ovarian cancer, BRCA1 mutations are as low as 9% in Iceland and as high as 79% in Russia. A similar variation has been documented for BRCA2 mutations as well, which can be exemplified by 8% in Finland and 64% in Iceland. In affected women before the age of 45 years with a first-degree relative, BRCA1 mutations account for 7% of the families [7]. In families with both male and female breast cancer, BRCA2 mutations were documented in 19% of North American, 33% of Hungarian and 90% of Icelandic populations [6]. In isolated male breast cancer cases, a very low frequency of BRCA2 mutations has been reported [8]. In early onset breast and/or ovarian cancer patients not selected for family history, 4–9% have BRCA1, and 2–8% have BRCA2 mutations 6, 7.
Breast cancer is among the most common malignancies in Turkish women [9]. The frequency and the types of germ line mutations involved in Turkish breast/ovarian cancers are not well known. In order to determine the contributions of BRCA1 and BRCA2 mutations to the development of breast and/or ovarian cancer in the Turkish population, we screened preselected regions of these genes in four groups of patients composed of hereditary and familial cancer, as well as early onset and male breast cancer.
Section snippets
Families
We analysed a total of 50 genomic DNA samples isolated from the white blood cells of breast cancer patients. The samples were collected from the Medical Schools of Hacettepe, Istanbul, Ankara Universities, and Ankara Oncology Hospital. Informed consent was obtained from all participants. Each proband was interviewed for pedigree construction including information concerning the family history of breast, ovarian and other cancers. Based on the pedigree analysis, patients were divided into four
Results
Germ line BRCA1 and/or BRCA2 mutations were screened in 50 breast and/or ovarian cancer patients from Turkey. We employed a BRCA1 and BRCA2 mutation screening strategy which is based on the localisation of previously reported mutations in these genes. Selected regions of BRCA1 (exons 2, 5, 11, 13, 20 and 24), and BRCA2 (exon 11) were subjected to heteroduplex analysis, and altered fragments were further analysed by DNA sequencing. According to the BIC database
Discussion
A wide variation in the BRCA1 and BRCA2 mutation spectrum and frequency has been reported for different populations [6]. The results of our Turkish data are summarised in Table 5. In the hereditary breast cancer group, BRCA2 mutations accounted for 33% of cases. This frequency is rather high and similar to the Icelandic population. Interestingly, BRCA1 mutations in our study group appear to be rare — if not exceptional, similar to patients from Iceland, Norway and Japan. However, in a recently
Acknowledgments
We thank Ms Lütfiye Mesci for oligonucleotide synthesis, and Dr Rengül Çetin Atalay for help in secondary structure prediction. This work was supported by grants from Bilkent Holding, TTGV, and TWAS. Hilal Özdag is a recipient of a TÜBITAK-BDP fellowship.
References (15)
- et al.
Population-based study of risk of breast cancer in carriers of BRCA2 mutation
Lancet
(1998) - et al.
Mutation analysis of BRCA1 and BRCA2 in Turkish cancer familiesa novel mutation BRCA2 3414del4 found in male breast cancer
Eur. J. Cancer
(1999) - et al.
Evidence for a third breast-cancer susceptibility gene
Lancet
(1994) - et al.
A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1
Science
(1994) La predisposition hereditaire au cancer du sein liee a BRCA1 et BRCA2une maladie de la reponse aux lesions genotoxiques
Medicine et Sciences
(1999)- et al.
Genetic linkage analysis in familial breast and ovarian cancerresults form 214 families
Am. J. Hum. Genet.
(1993) - et al.
Identification of the breast cancer susceptibility gene BRCA2
Nature
(1995)
Cited by (24)
Evaluation of hereditary/familial breast cancer patients with multigene targeted next generation sequencing panel and MLPA analysis in Turkey
2022, Cancer GeneticsCitation Excerpt :When the previous studies conducted in our country are reviewed, it seems difficult to make a generalization due to serious methodological differences (Table 4). Methods used in studies published before 2018 [11,12,13,14,15,16,17,18,19,20,21,27] mainly focused on heteroduplex scanning followed by confirmation by Sanger sequencing [11,12,13,15,16,20,21,27]. Additionally, protein truncation test [11,13,14], denaturing gradient gel electrophoresis [14,17], MLPA [18,19], western blot [20] and restriction enzyme digestion-based methods [14] were used as well.
Germline mutations of BRCA1 and BRCA2 genes in Turkish breast, ovarian, and prostate cancer patients
2010, Cancer Genetics and CytogeneticsCitation Excerpt :Only seven truncating mutations with a predicted deleterious effect on protein structure and function were detected among 156 families (∼5%). In previous studies regarding high-risk Turkish patients, as well as in the present study, overall mutation percentages range between 5% and 17%, with an average of ∼9% [11–17]. In most o3f these studies, analysis of only part of the genes was performed.
Identification of point mutations and large rearrangements in the BRCA1 gene in 667 Turkish unselected ovarian cancer patients
2010, Gynecologic OncologyCitation Excerpt :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 [10–15], 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.
Hereditary breast cancer syndromes in a Turkish population. Results of molecular germline analysis
2005, Cancer Genetics and CytogeneticsCitation Excerpt :To date, only a few reports have been published about the spectrum of BRCA1 and BRCA2 mutations in the Turkish population. No hotspot regions were reported [18–21]. Because these genes are rather large, mutation detection is laborious and expensive.
Polymorphisms in DNA repair and environmental interactions
2002, Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis