Balkan Journal of Medical Genetics

GENETIC VARIATION OF THE BRCA1 AND BRCA2 GENES IN MACEDONIAN PATIENTS
Maleva I1, Madjunkova S1, Bozhinovski G1, Smickova E2, Kondov G3, Spiroski Z3, Arsovski A4, Plaseska-Karanfilska D1,*
*Corresponding Author: Professor Dr. Dijana Plaseska-Karanfilska, Research Centre for Genetic Engineering and Biotechnology “Georgi D. Efremov,” Macedonian Academy of Sciences and Arts, Krste Misirkov 2, Skopje 1000, Republic of Macedonia; Tel: +389(0)2 3235410; Fax: +389 (0)2 3115434; E-mail: dijana@manu.edu.mk
page: 81

RESULTS AND DISCUSSION

Point mutations in the BRCA genes are the most common deleterious mutations in familial breast cancer patients. Complete sequencing remains the gold standard for initial mutation identification. However, large rearrangements in these genes have been described in a significant proportion of breast cancer families and are responsible for up to onethird of the identifiable BRCA mutations in a cer-tain population [12]. In our group of familial breast cancer patients (group 1 as defined in Materials and Methods), we identified a total of seven carriers of mutations: four point mutations and two large deletions in the BRCA1 gene and a point mutation in the BRCA2 gene (Table 1). Mutations appear to be evenly distributed across the coding sequence of the genes. Bearing in mind that certain mutations have been observed to be common to specific populations, we designed an assay for detection of the most common mutations in the Slavic populations. Our aim was to expand the mutation screen to breast cancer patients regardless of their family history. To this end, we developed a single nucleotide primer extension as a rapid and economical one-tube test for genetic testing of hereditary breast cancer that can be applied to a wider population setting (Figure 1, Table 2). We screened all sporadic patients and did not identify any mutations until now. More analyses including direct sequencing are needed in order to assess the distribution of mutations in the Macedonian population. This is important because it will allow the development of effective mutation-specific tests for the common mutations in the future. In patients with a strong familial history of breast cancer (n = 6), we performed mutational screening in all coding exons of the PALB2 gene using the high resolution melting (HRM) method. These analyses were performed at the Gynecology Unit, Hannover Medical School, Hannover, Germany. We found three already published polymorphisms and one potentially damaging variant. Many studies are focused on rare, highly penetrant germline mutations in BRCA genes that strongly predispose women to a familial form of breast cancer. However, there is a possibility that common germline variation in coding and non coding regions may also contribute to predisposition to breast cancer. In the present study, we tested seven common variations in the BRCA genes (Figure 2, Table 3) in all our patients in comparison to the controls. Our results showed that none of the polymorphisms tested were associated with the risk of sporadic breast cancer (group 3) suggesting that the variations per se do not play a significant role in the development of sporadic breast cancer. However,polymorphism rs8176267 in the BRCA1 gene showed an association with breast cancer risk when we analyzed the results for patients with at least one family member with breast cancer (groups 1 and 2 combined) vs. controls [p = 0.0151; OR (odds ratio) (95% CI) (95% confidence interval) = 2.31 (1.16- 4.61)]. These results are in concordance with published data [13]. Recent meta-analysis suggests that the BRCA2 N372H allele may be a low-penetrant risk factor for developing breast cancer [14], however, there is conflicting evidence regarding the role of this variant as a modifier of breast cancer risk. We observed that N372H is associated with slightly increased risk in patients with a family member with breast cancer [p = 0.0081; OR (95%CI) =2.37 (1.24-4.56)] [14]. Further analyses on larger cohorts of patients and controls are needed in order to build a highquality database of genetic BRCA1/2 gene variants in the Macedonian population, and to obtain accurate estimates as to the association of various polymorphisms with breast cancer risk.

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