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Breast Cancer Research and Treatment

, Volume 110, Issue 2, pp 343–348 | Cite as

I171V germline mutation in the NBS1 gene significantly increases risk of breast cancer

  • Krzysztof RożnowskiEmail author
  • Danuta Januszkiewicz-Lewandowska
  • Maria Mosor
  • Monika Pernak
  • Maria Litwiniuk
  • Jerzy Nowak
Clinical Trial

Abstract

Nijmegen Breakage Syndrome (NBS) is a rare autosomal, recessive disease caused by homozygous mutations in the NBS1 gene. The most common deletion of 5 bp (657del5) in exon 6, which affects mostly the population of Central Europe is observed. Among the typical features of this disorder is that NBS patients experience a high incidence of lymphoid malignancies as well. An increased risk of solid tumors development for 657del5 carriers was the reason to investigate the role of NBS1 gene as a susceptible one for the breast cancer. The purpose of this work is to identify mutations in all 16 exons of the NBS1 gene in the group of the patients with diagnosed breast cancer and the control group of healthy individuals. In the group of 270 women with breast cancer, seven cases of mutated NBS1 gene were revealed. In the subgroup presenting mutated NBS1 gene, the mutation I171V in 5th exon occurred in five cases. It is the first such a discovery concerning breast cancer patients because this mutation had been previously observed only in the course of lymphoid or hematological malignancies. The rate of I171V mutation in the group of breast cancer patients was significantly higher than in the controls (OR: 9.42; 95% CI: 1.09–81.05; = 0.02). The conclusion is that heterozygous germline mutation I171V in NBS1 gene is a significant risk factor for breast cancer development. It concerns especially the women whose first degree relatives had a previously diagnosed breast cancer (OR: 6.00; 95% CI: 0.98–38.07; P = 0.04). The histopathological and clinical features of breast cancer with I171V mutation suggest accumulation of the negative prognostic factors. The treatment’s results however were unexpectedly satisfactory, that is why further investigations are necessary to assess the role of I171V mutation in NBS1 gene as a prognostic and predictive factor for breast cancer.

Keywords

Breast cancer I171V mutation NBS1 gene 

References

  1. 1.
    Weemaes CM, Hustinx TW, Scheres JM et al (1981) A new chromosomal instability disorder: the Nijmegen breakage syndrome. Acta Paediatr Scand 70:557–564PubMedCrossRefGoogle Scholar
  2. 2.
    Seemanova E, Passarge E, Beneskova D et al (1985) Familial microcephaly with normal intelligence, immunodeficiency, and risk for lymphoreticular malignancies: a new autosomal recessive disorder. Am J Med Genet 20:639–648PubMedCrossRefGoogle Scholar
  3. 3.
    Steffen J, Varon R, Mosor M et al (2004) Increased cancer risk of heterozygotes with NBS1 germline mutations in Poland. Int J Cancer 111:67–71PubMedCrossRefGoogle Scholar
  4. 4.
    Cybulski C, Górski B, Dębniak T et al (2004) NBS1 is a prostate cancer susceptibility gene. Cancer Res 64:1215–1219PubMedCrossRefGoogle Scholar
  5. 5.
    Varon R, Seemanowa E, Chrzanowska K et al (2000) Clinical ascertainment of Nijmegen Breakage syndrome (NBS) and prevalence of the major mutation, 657del5, in three Slav populations. Eur J Hum Genet 8:900–902PubMedCrossRefGoogle Scholar
  6. 6.
    Ziółkowska I, Mosor M, Nowak J (2006) Regional distribution of heterozygous 657del5 mutation carriers of the NBS1 gene in Wielkopolska province (Poland). J Appl Genet 47:269–272PubMedGoogle Scholar
  7. 7.
    Steffen J, Nowakowska D, Niwińska A et al (2006) Germline mutation 657del5 of NBS1 gene contribute significantly to the incidence of breast cancer in Central Poland. Int J Cancer 119:472–475PubMedCrossRefGoogle Scholar
  8. 8.
    Cerosaletti KM, Lange E, Stringham HM et al (1998) Fine localization of the Nijmegen breakage syndrome gene to 8q21: evidence for a common founder haplotype. Am J Hum Genet 63:125–134PubMedCrossRefGoogle Scholar
  9. 9.
    Varon R, Reis A, Henze G, von Einsiedel HG et al (2001) Mutations in the Nijmegen Breakage Syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL). Cancer Res 61:3570–3572PubMedGoogle Scholar
  10. 10.
    Mosor M, Ziółkowska I, Pernak-Schwarz M (2006) I171V mutation of the NBS1 gene with childhood acute lymphoblastic leukemia. Leukemia 20:1454–1456PubMedCrossRefGoogle Scholar
  11. 11.
    Sheffield VC, Beck JS, Kwitek AE et al (1990) The sensivity of single-strand conformation polymorphism analysis for detection of single base substitution. Genomics 16:325–332CrossRefGoogle Scholar
  12. 12.
    Sanguinetti CJ, Dias Neto E, Simpson AJ (1994) Rapid silver staining and recovery of PCR products separated on olyacrylamide gels. Biotechniques 17:914–921PubMedGoogle Scholar
  13. 13.
    Varon R, Vissinga C, Platzer M et al (1998) Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 93:467–476PubMedCrossRefGoogle Scholar
  14. 14.
    Zhang Y, Zhou J, Lim CU (2006) The role of NBS1 in DNA double strand break repair, telomere stability, and cell cycle checkpoint control. Cell Res 16:45–54PubMedCrossRefGoogle Scholar
  15. 15.
    Tessitore A, Biordi L, Flati V et al (2003) New mutations and protein variants of NBS1 are identified in cancer cell lines. Genes, Chromosomes Cancer 36:198–204PubMedCrossRefGoogle Scholar
  16. 16.
    Tauchi H, Matsuura S, Kobayashi J (2002) Nijmegen breakage syndrome gene, NBS1, and molecular links to factors for genome stability. Oncogene 21:8967–8980PubMedCrossRefGoogle Scholar
  17. 17.
    Taylor GM, O’Brien HP, Greaves MF et al (2003) Letters to the editor. Cancer Res 63:6563–6564PubMedGoogle Scholar
  18. 18.
    Shimada H, Shimizu K, Mimaki S (2004) First case of aplastic anemia in a Japanese child with a homozygous missense mutation in the NBS1 gene (I171V) associated with genomic instability. Hum Genet 115:372–376PubMedCrossRefGoogle Scholar
  19. 19.
    Tauchi H, Kobayashi J, Morishima K et al (2002) Nbs1 is essential for DNA repair by homologous recombination in higher vertebrate cells. Nature 420:93–98PubMedCrossRefGoogle Scholar
  20. 20.
    Chrzanowska KH, Kleijer WJ, Krajewska-Walasek M et al (1995) Eleven Polish patients with microcephaly, immunodeficiency and chromosomal instability: the Nijmegen breakage syndrome. Am J Med Genet 57:462–471PubMedCrossRefGoogle Scholar
  21. 21.
    Stumm M, Neubauer S, Keindorff S et al (2001) High frequency of spontaneous translocations revealed by FISH in cells from patients with the cancer-prone syndromes ataxia teleangiectasia and Nijmegen breakage syndrome. Cytogenet Cell Genet 92:186–191PubMedCrossRefGoogle Scholar
  22. 22.
    Zhang Y, Lim CU, Williams ES et al (2005) NBS1 knockdown by small interfering RNA increases ionizing radiation mutagenesis and telomere association in human cells. Cancer Res 65:5544–5553PubMedCrossRefGoogle Scholar
  23. 23.
    Paz-y-Mino C, Sanchez ME, Del Pozo M et al (1997) Telomeric association in women with breast and uterine cervix cancer. Cancer Genet Cytogenet 98:115–118PubMedCrossRefGoogle Scholar
  24. 24.
    Zhu XD, Kuster B, Mann M et al (2000) Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Nat Genet 25:347–352PubMedCrossRefGoogle Scholar
  25. 25.
    Broeks A, Urbanus JH, Floore AN et al (2000) ATM – heterozygous germline mutations contribute to breast cancer-susceptibility. Am J Hum Genet 66:494–500PubMedCrossRefGoogle Scholar
  26. 26.
    Carlomagno F, Chang-Claude J, Dunning AM et al (1999) Determination of the frequency of the common 657del5 Nijmegen breakage syndrome mutation in German population: no association with risk of breast cancer. Genes Chromosomes Cancer 25:393–395PubMedCrossRefGoogle Scholar
  27. 27.
    Buslov KG, Iyevleva AG, Chekmariova EV et al (2005) NBS1 657del5 mutation may contribute only to a limited fraction of breast cancer cases in Russia. Int J Cancer 114:585–589PubMedCrossRefGoogle Scholar
  28. 28.
    Górski B, Dębniak T, Masojć B et al (2003) Germline 657del5 mutation in the NBS1 gene in breast cancer patients. Int J Cancer 106:379–381PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Krzysztof Rożnowski
    • 1
    Email author
  • Danuta Januszkiewicz-Lewandowska
    • 1
    • 2
  • Maria Mosor
    • 2
  • Monika Pernak
    • 2
  • Maria Litwiniuk
    • 1
  • Jerzy Nowak
    • 2
  1. 1.Klinika OnkologiiUniversity School of Medical SciencesPoznanPoland
  2. 2.Institute of Human Genetics, Polish Academy of SciencesPoznanPoland

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