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
page: 47

INTRODUCTION

Mutations in the BRCA1 and BRCA2 genes account for around 16.0-25.0% of high-risk familial breast cancers. Therefore, 75.0-84.0% of high-risk malignancies are not explained in terms of their genetic determinants. Part of the breast cancer cases could be attributed to genes that have moderate penetrance conferring 6.0-10.0% risk of developing the disease by the age of 60, compared with 3.0% for the general population [1]. Some of these genes encode for proteins that act in concert with each other in the intracellular DNA damage signaling and repair pathways. The CHEK2 and NBN genes belong to this group, and a few years ago were proposed to be attractive candidates for susceptibility genes for breast cancer development. The CHEK2 gene is located on chromosome 22q12.1 and encodes a G2 checkpoint kinase that plays a critical role in response to DNA damage by phosphorylating tumor suppressor proteins, including p53, Cdc25C, Cdc25A and BRCA1 [2]. The CHEK2 genetic variation in inherited cancer susceptibility was first indicated by Bell et al. [3] in 1999 who discovered CHEK2 1100delC (c.1100delC) germline mutation in patients with Li-Fraumeni syndrome. According to the meta-analysis provided by the CHEK2 Breast Cancer Case-Control Consortium, 1100delC is the most common CHEK2 mutation conferring a two-fold increase in risk for breast cancer and 10- fold increase for breast cancer in males. In addition, heterozygotes for the 1100delC allele have a six-fold elevated risk for bilateral breast cancer development [4,5]. There are conflicting results regarding the other rare CHEK2 mutations and their contribution to breast cancer susceptibility. The splice site mutation IVS2+1G>A (c.444+1G>A) results in a severely truncated CHEK2 protein lacking kinase activity, confers a three-fold risk for breast cancer. The mutation was observed to be associated with an increased risk for breast cancer in the Polish population [6], and has also been detected in the German [7,8] and Byelorussian populations as well [7]. Furthermore, a large CHEK2 deletion spanning exons 9 and 10 (del5395) has been described as a Czech founder mutation [9]and was also found in Poland [10]. The I157T (c.470T>C) missense variant, located within the FHA domain, have previously been reported to be pro oncogenic due to the protein inability to bind to downstream targets including BRCA1, Cdc25A, and p53. The frequency of the I157T variant varies between populations and the highest frequency was observed in Slavic populations. It confers around a 1.5-fold risk for breast cancer, but it is unclear whether it is sufficient to recommend testing in clinical practice [11]. The NBN (NBS1) gene is located on the 8q21.3 chromosome and encodes a protein that is a component of the MRE11/RAD50/NBN (MRN) complex involved in DNA double-strand break repair, telomere maintenance, and cell-cycle checkpoint control. Biallelic mutations in NBN are responsible for the majority of patients with Nijmegen breakage syndrome (NBS), a radiation sensitivity disorder characterized by microcephaly, growth retardation, immunodeficiency and a marked susceptibility to cancer [12]. Approximately 90.0% of NBS patients carry the homozygous mutation 657del5 (c.657_661delACAAA) in exon 6, which has been predominantly identified in Slavic populations and confers a three-fold risk for breast cancer development [13]. Association studies of NBN missense alterations in breast cancer series have not generally supported the hypothesis that amino acid substitutions could contribute to breast cancer susceptibility. However, the R215W (c.643C>T) substitution, is proposed to represent a cancer susceptibility allele with low penetrance in breast cancer, conferring around a two-fold risk for breast cancer development in carriers [14]. There are very limited data on the distribution and clinical relevance of CHEK2 and NBN mutations in the Balkan countries. We here report the clinical relevance of the most common mutations in CHEK2 and NBN genes for breast cancer development in Macedonian breast cancer patients. To the best of our knowledge, this is the first study to explore CHEK2 and NBN mutations in a large Balkan cohort.

Number 27 VOL. 27 (2), 2024	Number 27 VOL. 27 (1), 2024
Number 26 Number 26 VOL. 26(2), 2023 All in one	Number 26 VOL. 26(2), 2023
Number 26 VOL. 26, 2023 Supplement	Number 26 VOL. 26(1), 2023
Number 25 VOL. 25(2), 2022	Number 25 VOL. 25 (1), 2022
Number 24 VOL. 24(2), 2021	Number 24 VOL. 24(1), 2021
Number 23 VOL. 23(2), 2020	Number 22 VOL. 22(2), 2019
Number 22 VOL. 22(1), 2019	Number 22 VOL. 22, 2019 Supplement
Number 21 VOL. 21(2), 2018	Number 21 VOL. 21 (1), 2018
Number 21 VOL. 21, 2018 Supplement	Number 20 VOL. 20 (2), 2017
Number 20 VOL. 20 (1), 2017	Number 19 VOL. 19 (2), 2016
Number 19 VOL. 19 (1), 2016	Number 18 VOL. 18 (2), 2015
Number 18 VOL. 18 (1), 2015	Number 17 VOL. 17 (2), 2014
Number 17 VOL. 17 (1), 2014	Number 16 VOL. 16 (2), 2013
Number 16 VOL. 16 (1), 2013	Number 15 VOL. 15 (2), 2012
Number 15 VOL. 15, 2012 Supplement	Number 15 Vol. 15 (1), 2012
Number 14 14 - Vol. 14 (2), 2011	Number 14 The 9th Balkan Congress of Medical Genetics
Number 14 14 - Vol. 14 (1), 2011	Number 13 Vol. 13 (2), 2010
Number 13 Vol.13 (1), 2010	Number 12 Vol.12 (2), 2009
Number 12 Vol.12 (1), 2009	Number 11 Vol.11 (2),2008
Number 11 Vol.11 (1),2008	Number 10 Vol.10 (2), 2007
Number 10 10 (1),2007	Number 9 1&2, 2006
Number 9 3&4, 2006	Number 8 1&2, 2005
Number 8 3&4, 2004	Number 7 1&2, 2004
Number 6 3&4, 2003	Number 6 1&2, 2003
Number 5 3&4, 2002	Number 5 1&2, 2002
Number 4 Vol.3 (4), 2000	Number 4 Vol.2 (4), 1999
Number 4 Vol.1 (4), 1998	Number 4 3&4, 2001
Number 4 1&2, 2001	Number 3 Vol.3 (3), 2000
Number 3 Vol.2 (3), 1999	Number 3 Vol.1 (3), 1998
Number 2 Vol.3(2), 2000	Number 2 Vol.1 (2), 1998
Number 2 Vol.2 (2), 1999	Number 1 Vol.3 (1), 2000
Number 1 Vol.2 (1), 1999	Number 1 Vol.1 (1), 1998

About the journal ::: Editorial ::: Subscription ::: Information for authors ::: Contact