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

INTRODUCTION

The most significant and well characterized genetic risk factors for breast and/or ovarian cancer are germline mutations in the BRCA1 (17q chromosome) [1] and BRCA2 (13q chromosome) [2] genes. Other relevant genes, such as CHEK2, NBS1, PALB2, BRIP1, etc., also contribute to hereditary breast cancer, although their impact appears to be more population-specific [3]. It has been estimated that 5.0-10.0% of all breast cancer and 10.0-15.0% of ovarian cancer patients carry mutations on one of the BRCA genes [4]. The prevalence of the BRCA1/2 gene mutation carriers in the general population is approximately 0.2% (1/500), however, it can vary significantly in different countries and ethnic groups due to founder effects [5]. The mutations in these high-penetrance genes confer a high lifetime risk of breast and ovarian cancer. Women with an inherited BRCA1 gene mutation have a 65.0-80.0% risk of developing breast cancer and 37.0-62.0% of developing ovarian cancer over their lifetime, while BRCA2 gene mutation carriers have a 45.0-85.0% risk for breast cancer and 11.0-23.0% for ovarian cancer [6]. The identification of BRCA1 and BRCA2 gene mutation carriers is therefore a critical step in individualized risk assessment [7]. Once a mutation is identified in a given family, a very informative predictive (or presymptomatic) oncogenetic test can be offered to all adult family members. Moreover, oncogenetic testing is becoming the powerful therapeutic predictive tool, as new targeted therapeutic opportunities, such as poly(ADPribose) (PARP) inhibitors emerge [8] and chemosensitivity to platinum-based therapy is constantly reported [9]. It is now evident that in the near future the demand for rapid BRCA1/2 gene mutation testing will increase. However, a full BRCA1 and BRCA2 gene screening still remains a labor- and time-consuming challenge due to the large size of the genes and the high diversity of mutations and variants of unknown significance. On the other hand, the distribution of known BRCA1 and BRCA2 gene mutations is well documented worldwide. Several recent reviews have summarized the evidence that the BRCA1/2 gene mutation spectrum in given countries and ethnic communities is limited to a few founder mutations [4,5,10]. To date, no systematic study has assessed the distribution of BRCA1/2 gene mutations in the Macedonian population. We aimed to initiate screening for BRCA1/2 gene mutations in order to identify the genetic variants common in the Republic of Macedonia. The fact that BRCA1 and BRCA2 gene mutations drastically increase breast cancer risk suggests that polymorphisms in these genes could represent low penetrance susceptibility alleles [11]. Whether common polymorphisms contribute to disease risk has not yet been thoroughly evaluated. The importance of these common variants is still conflicting and more data on large cohorts are needed to better understand their significance. We present data on several single nucleotide polymorphisms (SNPs) including allele frequencies and association with breast cancer risk.

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