Balkan Journal of Medical Genetics

CLINICAL RELEVANCE OF CHEK2 AND NBN MUTATIONS IN THE MACEDONIAN POPULATION
Maleva Kostovska I, Jakimovska M, Kubelka-Sabit K, Karadjozov M, Arsovski A, Stojanovska L, Plaseska-Karanfilska D1,
*Corresponding Author: Dijana Plaseska-Karanfilska, M.D., Ph.D., Research Centre for Genetic Engineering and Biotechnology “Geogi D. Efremov,” Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia. Tel: +389-2-3235-410. Fax: +389-2-3155-434. E-mail: dijana@manu.edu.mk
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DISCUSSION

There is no universal consensus regarding the importance of CHEK2 and NBN mutations in breast cancer development. Our study was aimed to contribute to the knowledge of their role in breast cancer development in patients from Southern Europe by providing the first data for this geographic region. Surprisingly, we found very low frequencies of the selected mutations in the Macedonian population, which were not in agreement with some previously published data on Slavic populations. Although it is very rare, the 1100delC mutation in CHEK2 is the most studied, showing wide variation in the frequency in different populations. Highest frequencies of this mutations in breast cancer patients have been found in The Netherlands (2.9 in patients vs. 1.6% in controls) [16], Finland (2.0 vs. 1.0%) [4], and lower in Sweden (1.3 vs. 0.6%) [17], Denmark (1.2 vs. 0.5%) [18], USA (1.1 vs. 0.4%) [19], Germany (0.8 vs. 0.5%) [20], Poland (0.5 vs. 0.2%) [10] and Czech Republic (0.4 vs. 0.3%) [21].We observed only one 1100delC mutation carrier, thus showing that the clinical importance of the mutation for the Macedonian population is minor. It was unexpected that we did not detect the IVS2+1G>A mutation and the 5395 bp deletion in our cohort. Though our results are partially in agreement with the data from a small study of 57 HBOC (high grade breast and ovarian cancer) cases in Serbia, where 1100delC was not observed, and only one 5395bp deletion carrier was identified [22]. IVS2+1G>A was identified as a Polish founder mutation with a frequency of 0.3% in the general population and 1.2% in breast cancer patients [6]. It was also observed in German (0.0-0.4%) [7,8] and Byelorussian populations (0.2%) [7]. The 5395 del was reported as a founder mutation in Poland with 0.4% population frequency [10]. Bogdanova et al. [23] found IVS2+1G>A in Byelorussian (0.9%) and in German breast cancer patients (0.5%). The studies indicating the relevance of the I157T missense mutation in elevating the risk of developing breast cancer disagreed: either showing an increased risk for breast cancer [7,24-26] or no association with the disease [8,27]. I157T was observed with the highest frequency in two separate studies in Poland (9.3 in breast cancer cases vs. 5.8% in controls and 7.6 vs. 5.1%) [24,25], Poland and Belarus together (5.5 vs. 3.4%) [26], Belarus (5.6 vs. 1.3%) [7]. Less frequent and without any clinical significance, the variant was observed in Germany (1.9 vs. 1.6%) [8] and Czech Republic (2.8 vs. 2.5%) [27]. In our studied population, I157T was twice as frequent in the patient group (3.0 vs. 1.4%), although statistical significance was not reached (p = 0.176). When familial vs. non familial breast cancer history patients were compared, the variant was found to be associated with familial breast cancer (p = 0.041). The 657del5 germline mutation in NBN accounts for more than 90.0% of all mutant alleles in the gene. The highest frequency of heterozygous carriers was found in the Slavic population from Central Europe with an average frequency of 1/177 [13]. Gorski et al. [28] found 657del5 in 0.8% of studied breast cancer cases and in 0.6% of the controls in Poland. Similarly, Steffen et al. [29] found the mutation in 1.96% unselected breast cancer patients in central Poland and 0.62% in controls. Bogdanova et al. performed large-scale analysis of breast cancerpatients and controls fromBelarus and Northern Germany. They confirmed that 657del5 was clearly associated with an increased breast cancer risk in both populations, Belorussian (0.9% in patients vs. 0.1% in controls) and German (0.1% in patients and 0% in controls) [14]. The R215W mutation was once considered a polymorphism of NBN, and its severe pathogenicity only emerged with the identification of compound heterozygous 657del5/R215W NBS patients. Still there are conflicting opinions whether it does represent a cancer susceptibility allele. Bogdanova et al. [14] observed that the R215W substitution may be an allele with lower penetrance for breast cancer development in Northern Germany (0.8 in patients vs. 0.2% in controls), but not in Belorussia (0.6 in patients vs. 0.5% in controls). We did not confirm that 657del5 and R215W represent breast cancer risk alleles and our results are in agreement with the results published by Carlomagno et al. [30] and Mateju et al. [31]. Carlomagno et al. [30] performed a large study in the German population and found one 657 del5 mutation in 477 patients (0.21%) and one in 866 controls (0.12%). In addition, Mateju et al. [31] identified two carriers of the 657del5 mutation in 703 analyzed cases (0.28%) and two in 913 controls (0.22%), while they found R215W in three patients (0.43%) and four controls (0.44%) in a Czech cohort. In conclusion, the frequencies of the NBN 657del5 and R215W mutations in the Macedonian population are low, and no association of these mutations with breast cancer susceptibility was demonstrated. In summary, we have analyzed the impact of the most common mutations in CHEK2 and NBN genes on breast cancer development in Macedonian breast cancer patients. We showed that the frequencies of the studied mutations are very low and they do not seem to represent alleles of high clinical importance in our population. Our study is the first to explore CHEK2 and NBN mutations in a large Balkan cohort. It would be of great interest to assess the distribution of these mutations in other Balkan countries. We also established one-tube multiplex PCR for screening all five CHEK2 and NBN mutations in one reaction, which can be used as a fast screening method in populations where these mutations are more common and with clinical relevance. Declaration of Interest. This study was supported by the Macedonian Academy of Sciences and Arts, Skopje, Macedonia. IMK designed the experiments, performed the analysis and wrote the manuscript; MJ participated in performing the analysis. KKS, MK, AA and LS were involved in recruitment of participants and obtaining informed consent from them. DPK conceived and designed the study. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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