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      Clinical relevance of CHEK2 and NBN mutations in the macedonian population


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          Clinical importance of the most common CHEK2 (IVS2+1 G>A, 1100delC, I157T and del5395) and NBN (R215W and 657del5) gene mutations for breast cancer development in Macedonian breast cancer patients is unknown. We performed a case-control study including 300 Macedonian breast cancer patients and 283 Macedonian healthy controls. Genotyping was done using a fast and highly accurate single-nucleotide primer extension method for the detection of five mutations in a single reaction. The detection of the del5395 was performed using an allele-specific duplex polymerase chain reaction (PCR) assay. We have found that mutations were more frequent in breast cancer patients ( n = 13, 4.3%) than in controls ( n = 5, 1.8%), although without statistical significance. Twelve patients were heterozygous for one of the analyzed mutations, while one patient had two mutations ( NBN R215W and CHEK2 I157T). The most frequent variant was I157T, found in 10 patients and four controls ( p = 0.176) and was found to be associated with familial breast cancer ( p = 0.041). CHEK2 1100delC and NBN 657del5 were each found in one patient and not in the control group. CHEK2 IVS2+1G>A and del5395 were not found in our cohort. Frequencies of the studied mutations are low and they are not likely to represent alleles of clinical importance in the Macedonian population.

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          Most cited references 31

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          The emerging landscape of breast cancer susceptibility.

          The genetic basis of inherited predisposition to breast cancer has been assiduously investigated for the past two decades and has been the subject of several recent discoveries. Three reasonably well-defined classes of breast cancer susceptibility alleles with different levels of risk and prevalence in the population have become apparent: rare high-penetrance alleles, rare moderate-penetrance alleles and common low-penetrance alleles. The contribution of each component to breast cancer predisposition is still to be fully explored, as are the phenotypic characteristics of the cancers associated with them, the ways in which they interact, much of their biology and their clinical utility. These recent advances herald a new chapter in the exploration of susceptibility to breast cancer and are likely to provide insights relevant to other common, heterogeneous diseases.
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            Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.

            Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. Cells from NBS patients are hypersensitive to ionizing radiation with cytogenetic features indistinguishable from ataxia telangiectasia. We describe the positional cloning of a gene encoding a novel protein, nibrin. It contains two modules found in cell cycle checkpoint proteins, a forkhead-associated domain adjacent to a breast cancer carboxy-terminal domain. A truncating 5 bp deletion was identified in the majority of NBS patients, carrying a conserved marker haplotype. Five further truncating mutations were identified in patients with other distinct haplotypes. The domains found in nibrin and the NBS phenotype suggest that this disorder is caused by defective responses to DNA double-strand breaks.
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              Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome.

              The hCHK2 gene encodes the human homolog of the yeast Cds1 and Rad53 G2 checkpoint kinases, whose activation in response to DNA damage prevents cellular entry into mitosis. Here, it is shown that heterozygous germ line mutations in hCHK2 occur in Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in the TP53 gene. These observations suggest that hCHK2 is a tumor suppressor gene conferring predisposition to sarcoma, breast cancer, and brain tumors, and they also provide a link between the central role of p53 inactivation in human cancer and the well-defined G2 checkpoint in yeast.

                Author and article information

                Balkan J Med Genet
                Balkan J. Med. Genet
                Balkan Journal of Medical Genetics : BJMG
                Macedonian Science of Sciences and Arts
                June 2015
                30 December 2015
                : 18
                : 1
                : 47-54
                [1 ]Research Centre for Genetic Engineering and Biotechnology “Georgi D. Efremov,” Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia
                [2 ]“Adzibadem-Sistina” Hospital, Skopje, Republic of Macedonia
                [3 ]“Re-Medika” Hospital, Skopje, Republic of Macedonia
                Author notes
                [* ] 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@ 123456manu.edu.mk
                © Macedonian Academy of Sciences and Arts

                This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivs license ( http://creativecommons.org/licenses/by-nc-nd/3.0/), which means that the text may be used for non-commercial purposes, provided credit is given to the author.

                Original Article

                breast cancer, chek2, macedonian population, mutations, nbn


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