Advertisement

Breast Cancer Research and Treatment

, Volume 102, Issue 1, pp 119–122 | Cite as

A deletion in CHEK2 of 5,395 bp predisposes to breast cancer in Poland

  • Cezary Cybulski
  • Dominika Wokołorczyk
  • Tomasz Huzarski
  • Tomasz Byrski
  • Jacek Gronwald
  • Bohdan Górski
  • Tadeusz Dębniak
  • Bartłomiej Masojć
  • Anna Jakubowska
  • Thierry van de Wetering
  • Steven A. Narod
  • Jan Lubiński
Epidemiology

Abstract

To investigate the contribution of a founder deletion in the CHEK2 gene to the burden of breast cancer in Poland we studied 4,454 women with breast cancer and 5,496 population controls. Cases and controls were genotyped for the presence of a 5,395 bp founder deletion that removes exons 9 and 10 of the CHEK2 gene. This deletion has recently been described in a Czech and Slovak population. The cases and controls had previously been tested for two protein-truncating (IVS2 + 1G > A and 1100delC) and one missense CHEK2 mutation (I157T) which are characteristic for the population. The exons 9 and 10 deletion was present in 0.4% of the controls, in 1.0% (19 of 1,978) of unselected breast cancer cases (OR=2.2; 95% CI: 1.2–4.0; p = 0.01) and in 0.9% (28 of 3,228) of the early-onset cases (OR=2.0; 95% CI: 1.3–1.8; p = 0.02). One of the three truncating CHEK2 mutations (del5395; 1100delC or IVS2 + 1G > A) was seen in 101 of 4,454 (2.3%) cases and in 58 of 5,496 controls (1.1%) (OR=2.2; 95% CI: 1.6–3.0 p < 0.0001). A 5,395 bp founder deletion contributes to the burden of breast cancer in Poland. The deletion was present in 0.9% of the women with breast cancer diagnosed under the age of 51 and in 0.9% of women with breast cancer over the age of 50. This is one of the most common protein-truncating CHEK2 variants in Poland. Overall, 2% of all breast cancers in Poland can be attributed to one of three protein-truncating mutatiosns in CHEK2.

Keywords

Breast cancer CHEK2 gene CHK2 gene Germline mutation Large deletion 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Notes

Acknowledgements

We thank the following people who helped in this study: Uciński M., Grzybowska E., Lange D., Mika B., Mackiewicz A., Karczewska A., Breborowicz J., Lamperska K., Stawicka M., Gozdecka-Grodecka S., Bębenek M., Sorokin D., Wojnar A., Haus O., Sir J., Mierzwa T., Niepsuj S., Gugała K., Goźdź S., Sygut J., Kozak-Klonowska B., Musiatowicz B., Posmyk M., Kordek R., Morawiec M., Zambrano O., Waśko B., Fudali L., Surdyka D., Urbański K., Mituś J., Ryś J., Szwiec M., Rozmiarek A., Dziuba I., Wandzel P., Wiśniowski R., Szczylik C., Kozak A., Kozłowski A., Czajka R., Czeszyńska B., Dębniak B., Brembowicz G., Kalużewski B., Witek A., Skret A., Lenczewski A., Wonton J. and Gibaszek R.

References

  1. 1.
    Matsuoka S, Rotman G, Ogawa A, Shiloh Y, Tamai K, Elledge SJ (2000) Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proc Natl Acad Sci USA 97:10389–10394PubMedCrossRefGoogle Scholar
  2. 2.
    Chaturvedi P, Eng WK, Zhu Y et al. (1999) Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway. Oncogene 18:4047–4054PubMedCrossRefGoogle Scholar
  3. 3.
    CHEK2 Breast Cancer Consortium (2002) Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31:55–59CrossRefGoogle Scholar
  4. 4.
    Oldenburg RA, Kroeze-Jansema K, Kraan J et al. (2003) The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families. Cancer Res 63:8153–8157PubMedGoogle Scholar
  5. 5.
    Vahteristo P, Bartkova J, Eerola H et al (2002) A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet 71:432–438PubMedCrossRefGoogle Scholar
  6. 6.
    CHEK2 Breast Cancer Case–Control Consortium (2004) CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am J Hum Genet 74:1175–1182CrossRefGoogle Scholar
  7. 7.
    Cybulski C, Gorski B, Huzarski T et al. (2004) CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 75:1131–1135PubMedCrossRefGoogle Scholar
  8. 8.
    Kilpivaara O, Vahteristo P, Falck J et al. (2004) CHEK2 variant I157T may be associated with increased breast cancer risk. Int J Cancer 111:543–547PubMedCrossRefGoogle Scholar
  9. 9.
    Shaag A, Walsh T, Renbaum P et al. (2005) CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population. Hum Mol Genet 14:555–563PubMedCrossRefGoogle Scholar
  10. 10.
    de Bock GH, Schutte M, Krol-Warmerdam EM et al. (2004) Tumour characteristics and prognosis of breast cancer patients carrying the germline CHEK2*1100delC variant. J Med Genet 41:731–735PubMedCrossRefGoogle Scholar
  11. 11.
    Allinen M, Huusko P, Mantyniemi S, Launonen V, Winqvist R (2001) Mutation analysis of the CHK2 gene in families with hereditary breast cancer. Br J Cancer 85:209–212PubMedCrossRefGoogle Scholar
  12. 12.
    Schutte M, Seal S, Barfoot R et al. (2003) Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility. Am J Hum Genet 72:1023–1028PubMedCrossRefGoogle Scholar
  13. 13.
    Bogdanova N, Enssen-Dubrowinskaja N, Feshchenko S et al (2005) Association of two mutations in the CHEK2 gene with breast cancer. Int J Cancer 116:263–266PubMedCrossRefGoogle Scholar
  14. 14.
    Gorski B, Cybulski C, Huzarski T et al. (2005) Breast cancer predisposing alleles in Poland. Breast Cancer Res Treat 92:19–24PubMedCrossRefGoogle Scholar
  15. 15.
    Walsh T, Casadei S, Coats KH et al. (2006) Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295:1379–1388PubMedCrossRefGoogle Scholar
  16. 16.
    Cybulski C, Huzarski T, Górski B et al (2004) A novel founder CHEK2 mutation is associated with increased prostate cancer risk. Cancer Res 64:2677–2679PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  • Cezary Cybulski
    • 1
  • Dominika Wokołorczyk
    • 1
  • Tomasz Huzarski
    • 1
  • Tomasz Byrski
    • 1
  • Jacek Gronwald
    • 1
  • Bohdan Górski
    • 1
  • Tadeusz Dębniak
    • 1
  • Bartłomiej Masojć
    • 1
  • Anna Jakubowska
    • 1
  • Thierry van de Wetering
    • 1
  • Steven A. Narod
    • 2
  • Jan Lubiński
    • 1
  1. 1.Department of Genetics and Pathology, International Hereditary Cancer CenterPomeranian Medical UniversitySzczecinPoland
  2. 2.Centre for Research on Women’s HealthTorontoCanada

Personalised recommendations