Heterozygous p.I171V mutation of the NBN gene as a risk factor for lung cancer development

Kałużna,Ewelina  Maria; Rembowska,Jolanta; Ziółkowska‑Suchanek,Iwona; Świątek‑Kościelna,Bogna; Gabryel,Piotr; Dyszkiewicz,Wojciech; Nowak,Jerzy  Stanisław

doi:10.3892/ol.2015.3715

Heterozygous p.I171V mutation of the NBN gene as a risk factor for lung cancer development

Authors:
- Ewelina Maria Kałużna
- Jolanta Rembowska
- Iwona Ziółkowska‑Suchanek
- Bogna Świątek‑Kościelna
- Piotr Gabryel
- Wojciech Dyszkiewicz
- Jerzy Stanisław Nowak
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Affiliations: Department of Molecular Pathology, Institute of Human Genetics of the Polish Academy of Sciences, Poznań 60‑479, Poland, Department of Thoracic Surgery, University of Medical Sciences, Poznań 60‑569, Poland
Published online on: September 17, 2015 https://doi.org/10.3892/ol.2015.3715
Pages: 3300-3304

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Abstract

The NBN gene, also known as NBS1, is located on the chromosome band 8q21.3, and encodes a 754‑amino acid‑long protein named nibrin. This protein is a member of the MRE1‑RAD50‑NBN nuclear complex, and is involved in numerous cell processes essential for maintaining genomic stability. Heterozygous variants in the NBN gene, including p.I171V, c.657del5 and p.R215W, have been described as risk factors for the development of several malignancies. However, there is no report regarding the association of these mutations with lung cancer thus far. Therefore, the present study aimed to evaluate whether there is an association between the heterozygous p.I171V, c.657del5 and p.R215W variants of the NBN gene and the risk of developing lung cancer. The frequency of these variants was estimated in a group of 453 adults diagnosed with non‑small cell lung cancer (NSCLC) and in healthy controls (2,400 for p.I171V, 2,090 for c.657del5 and 498 for p.R215W). The p.I171V variant was assessed by restriction fragment length polymorphism analysis of polymerase chain reaction (PCR) products, using MunI (MfeI) restriction enzyme, whereas the c.657del5 and p.R215W variants were assessed by the PCR single‑strand conformation polymorphism method. A significantly increased risk of developing lung cancer was observed for the p.I171V variant, which was present in 17 (3.75%) of the 453 cases of lung cancer and in 12 (0.5%) of the 2,400 healthy individuals (odds ratio, 7.759; P<0.0001). The results obtained indicated an association between the p.I171V mutation and the development of lung cancer. Therefore, this variant may be considered a risk factor for NSCLC. Prospective studies with larger groups of patients may reveal the potential impact of the p.I171V variant in the occurrence of lung cancer.

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1	Weizmann Institute of Science: GeneCards: NBN gene. Rehovot, Israel: Weizmann Institute of Science. 2014.
2	Assenmacher N and Hopfner KP: MRE11/RAD50/NBS1: Complex activities. Chromosoma. 113:157–166. 2004. View Article : Google Scholar : PubMed/NCBI
3	D'Amours D and Jackson SP: The Mre11 complex: At the crossroads of dna repair and checkpoint signalling. Nat Rev Mol Cell Biol. 3:317–327. 2002. View Article : Google Scholar : PubMed/NCBI
4	Tauchi H, Matsuura S, Kobayashi J, Sakamoto S and Komatsu K: Nijmegen breakage syndrome gene, NBS1, and molecular links to factors for genome stability. Oncogene. 21:8967–8980. 2002. View Article : Google Scholar : PubMed/NCBI
5	Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M, Yates JR III, Hays L, Morgan WF and Petrini JH: The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: Linkage of double-strand break repair to the cellular DNA damage response. Cell. 93:477–486. 1998. View Article : Google Scholar : PubMed/NCBI
6	Matsuura S, Tauchi H, Nakamura A, Kondo N, Sakamoto S, Endo S, Smeets D, Solder B, Belohradsky BH, Der Kaloustian VM, et al: Positional cloning of the gene for Nijmegen breakage syndrome. Nat Genet. 19:179–181. 1998. View Article : Google Scholar : PubMed/NCBI
7	Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K, Beckmann G, Seemanová E, Cooper PR, Nowak NJ, et al: Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell. 93:467–476. 1998. View Article : Google Scholar : PubMed/NCBI
8	Mosor M, Ziółkowska I, Pernak-Schwarz M, Januszkiewicz-Lewandowska D and Nowak J: Association of the heterozygous germline I171V mutation of the NBS1 gene with childhood acute lymphoblastic leukemia. Leukemia. 20:1454–1456. 2006. View Article : Google Scholar : PubMed/NCBI
9	Roznowski K, Januszkiewicz-Lewandowska D, Mosor M, Pernak M, Litwiniuk M and Nowak J: I171V germline mutation in the NBS1 gene significantly increases risk of breast cancer. Breast Cancer Res Treat. 110:343–348. 2008. View Article : Google Scholar : PubMed/NCBI
10	Ziólkowska I, Mosor M, Wierzbicka M, Rydzanicz M, Pernak-Schwarz M and Nowak J: Increased risk of larynx cancer in heterozygous carriers of the I171V mutation of the NBS1 gene. Cancer Sci. 98:1701–1705. 2007. View Article : Google Scholar : PubMed/NCBI
11	Nowak J, Mosor M, Nowicka K, Rembowska J and Januszkiewicz D: Is the NBN gene mutation I171V a potential risk factor for malignant solid tumors in children? J Pediatr Hematol Oncol. 33:e248–e249. 2011. View Article : Google Scholar : PubMed/NCBI
12	Cybulski C, Górski B, Debniak T, Gliniewicz B, Mierzejewski M, Masojć B, Jakubowska A, Matyjasik J, Złowocka E, Sikorski A, et al: NBS1 is a prostate cancer susceptibility gene. Cancer Res. 64:1215–1219. 2004. View Article : Google Scholar : PubMed/NCBI
13	Mosor M, Ziółkowska-Suchanek I, Nowicka K, Dzikiewicz-Krawczyk A, Januszkiewicz-Lewandowska D and Nowak J: Germline variants in MRE11/RAD50/NBN complex genes in childhood leukemia. BMC Cancer. 13:457–464. 2013. View Article : Google Scholar : PubMed/NCBI
14	Ziółkowska I, Mosor M and Nowak J: Regional distribution of heterozygous 657del5 mutation carriers of the NBS1 gene in Wielkopolska province (Poland). J Appl Genet. 47:269–272. 2006. View Article : Google Scholar : PubMed/NCBI
15	Nowak J, Mosor M, Ziółkowska I, Wierzbicka M, Pernak-Schwarz M, Przyborska M, Roznowski K, Pławski A, Słomski R and Januszkiewicz D: Heterozygous carriers of the I171V mutation of the NBS1 gene have a significantly increased risk of solid malignant tumours. Eur J Cancer. 44:627–630. 2008. View Article : Google Scholar : PubMed/NCBI
16	Gao P, Ma N, Li M, Tian Q-B and Liu DW: Functional variants in NBS1 and cancer risk: Evidence from a meta-analysis of 60 publications with 11 individual studies. Mutagenesis. 28:683–697. 2013. View Article : Google Scholar : PubMed/NCBI
17	Bork P, Hofmann K, Bucher P, Neuwald AF, Altschul SF and Koonin EV: A superfamily of conserved domains in DNA damage-responsive cell cycle checkpoint proteins. FASEB J. 11:68–76. 1997.PubMed/NCBI
18	Cerosaletti KM and Concannon P: Nibrin forkhead-associated domain and breast cancer C-terminal domain are both required for nuclear focus formation and phosphorylation. J Biol Chem. 278:21944–21951. 2003. View Article : Google Scholar : PubMed/NCBI
19	Ciara E, Piekutowska-Abramczuk D, Popowska E, Grajkowska W, Barszcz S, Perek D, Dembowska-Bagińska B, Perek-Polnik M, Kowalewska E, Czajńska A, et al: Heterozygous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients. Acta Neuropathol. 119:325–334. 2010. View Article : Google Scholar : PubMed/NCBI
20	Dzikiewicz-Krawczyk A, Mosor M, Januszkiewicz D and Nowak J: Impact of heterozygous c.657-661del, p.I171V and p.R215W mutations in NBN on nibrin functions. Mutagenesis. 27:337–343. 2012. View Article : Google Scholar : PubMed/NCBI
21	Seemanová E, Jarolim P, Seeman P, Varon R, Digweed M, Swift M and Sperling K: Cancer risk of heterozygotes with the NBN founder mutation. J Natl Cancer Inst. 99:1875–1880. 2007. View Article : Google Scholar : PubMed/NCBI
22	Steffen J, Varon R, Mosor M, Maneva G, Maurer M, Stumm M, Nowakowska D, Rubach M, Kosakowska E, Ruka W, et al: Increased cancer risk of heterozygotes with NBS1 germline mutations in Poland. Int J Cancer. 111:67–71. 2004. View Article : Google Scholar : PubMed/NCBI
23	Seemanová E, Sperling K, Neitzel H, Varon R, Hadac J, Butova O, Schröck E, Seeman P and Digweed M: Nijmegen breakage syndrome (NBS) with neurological abnormalities and without chromosomal instability. J Med Genet. 43:218–224. 2006. View Article : Google Scholar : PubMed/NCBI
24	Varon R, Reis A, Henze G, von Einsiedel HG, Sperling K and Seeger K: Mutations in the Nijmegen Breakage Syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL). Cancer Res. 61:3570–3572. 2001.PubMed/NCBI
25	Hebbring SJ, Fredriksson H, White KA, Maier C, Ewing C, McDonnell SK, Jacobsen SJ, Cerhan J, Schaid DJ, Ikonen T, et al: Role of the Nijmegen breakage syndrome gene in familial and sporadic prostate cancer. Cancer Epidemiol Biomarkers Prev. 15:935–938. 2006. View Article : Google Scholar : PubMed/NCBI