Familial Cancer

, 8:473 | Cite as

Haplotypes of the I157T CHEK2 germline mutation in ethnically diverse populations

  • Bella Kaufman
  • Yael Laitman
  • Jacek Gronwald
  • Robert Winqvist
  • Arvids Irmejs
  • Jan Lubinski
  • Katri Pylkäs
  • Janis Gardovskis
  • Edvins Miklasevics
  • Eitan FriedmanEmail author


The CHEK2*I157T missense mutation, reported in ethnically diverse, high-risk families, moderately increases breast and colon cancer risk. The present study assessed whether this mutation represents a founder mutation. Participants identified in high risk clinics or from consecutive cancer patients in Israel, Poland, Latvia, and Finland, were either carriers of the CHEK2*I157T mutation or non-carrier family members. Multi-locus genotyping employed two intragenic markers and five CHEK2 gene flanking markers, spanning about 645 kb. Haplotyping was done when families were available for phasing. Overall, 101 individuals (83 I157T*CHEK2 mutation carriers) were genotyped: 16 Finnish individuals from 11 families (14 mutation carriers, two non-carrier family members), 50 Polish individuals (20 families) (35 carriers, 15 non-carriers), 28 unrelated Latvian mutation carriers, and seven Israeli participants (two families) (six mutation carriers, one non-carrier). Overall 36/83 mutation carriers (43%) were diagnosed with breast cancer, 15/83 (18%)—colon cancer, three—ovarian cancer, one—thyroid cancer, and the rest (n = 28) were asymptomatic. A common core haplotype was detected in all I157T*CHEK2 mutation carriers of Israeli, Polish, and Finnish origin between markers D22S275-D22S689 (~258 kb), with a different allele pattern in Latvians. In conclusion, CHEK2*I157T missense mutation is a founder mutation in ethnically diverse populations, but may also be a mutational hotspot.


CHEK2 gene Founder mutation Germline mutations Haplotype High risk cancer families 



This grant was partially funded by a grant from the Tel-Aviv University to Eitan Friedman


  1. 1.
    Antoniou A, Pharoah PD, Narod S et al (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72:1117–1130CrossRefPubMedGoogle Scholar
  2. 2.
    Anglian Breast Cancer Study Group (2000) Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Br J Cancer 83:1301–1308CrossRefGoogle Scholar
  3. 3.
    Walsh T, King MC (2007) Ten genes for inherited breast cancer. Cancer Cell 11:103–105CrossRefPubMedGoogle Scholar
  4. 4.
    Brown AL, Lee CH, Schwarz JK et al (1999) A human Cds1-related kinase that functions downstream of ATM protein in the cellular response to DNA damage. Proc Natl Acad Sci USA 96:3745–3750CrossRefPubMedGoogle Scholar
  5. 5.
    Lee JS, Collins KM, Brown AL et al (2000) hCds1- mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 404:201–204CrossRefPubMedGoogle Scholar
  6. 6.
    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
  7. 7.
    Meijers-Heijboer H, van den Ouweland A, Klijn J et al (2002) Low penetrance susceptibility of breast cancer due to CHEK2*1100delC in non-carriers of BRCA1 or BRCA2 mutations. Nat Genet 31:55–59CrossRefPubMedGoogle Scholar
  8. 8.
    Weischer M, Bojesen SE, Tybjaerg-Hansen A et al (2007) Increased risk of breast cancer associated with CHEK2*1100delC. J Clin Oncol 25:57–63CrossRefPubMedGoogle Scholar
  9. 9.
    Sodha N, Mantoni TS, Tavtigian SV et al (2006) Rare germ line CHEK2 variants identified in breast cancer families encode proteins that show impaired activation. Cancer Res 66:8966–8970CrossRefPubMedGoogle Scholar
  10. 10.
    Bell DW, Kim SH, Godwin AK et al (2007) Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts. Int J Cancer 121:2661–2667CrossRefPubMedGoogle Scholar
  11. 11.
    Shaag A, Walsh T, Renbaum P et al (2005) Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population. Hum Mol Genet 14:555–563CrossRefPubMedGoogle Scholar
  12. 12.
    Nevanlinna H, Bartek J (2006) The CHEK2 gene and inherited breast cancer susceptibility. Oncogene 25:5912–5919CrossRefPubMedGoogle Scholar
  13. 13.
    Falck J, Mailand N, Syljuasen RG et al (2001) The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410:842–847CrossRefPubMedGoogle Scholar
  14. 14.
    Li J, Williams BL, Haire LF et al (2002) Structural and functional versatility of the FHA domain in DNA-damage signaling by the tumor suppressor kinase Chk2. Mol Cell 9:1045–1049CrossRefPubMedGoogle Scholar
  15. 15.
    Falck J, Lukas C, Protopopova M et al (2001) Functional impact of concomitant versus alternative defects in the Chk2–p53 tumour suppressor pathway. Oncogene 20:5503–5510CrossRefPubMedGoogle Scholar
  16. 16.
    Cybulski C, Wokołorczyk D, Kładny J et al (2007) Germline CHEK2 mutations and colorectal cancer risk: different effects of a missense and truncating mutations? Eur J Hum Genet 15:237–241CrossRefPubMedGoogle Scholar
  17. 17.
    Kilpivaara O, Alhopuro P, Vahteristo P et al (2006) CHEK2 I157T associates with familial and sporadic colorectal cancer. J Med Genet 43:e34CrossRefPubMedGoogle Scholar
  18. 18.
    Bogdanova N, Enssen-Dubrowinskaja N, Feshchenko S et al (2005) Association of two mutations in the CHEK2 gene with breast cancer. Int J Cancer 116:263–266CrossRefPubMedGoogle Scholar
  19. 19.
    Thorlacius S, Olafsdottir G, Tryggvadottir L et al (1996) A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet 13:117–119CrossRefPubMedGoogle Scholar
  20. 20.
    Roa BB, Boyd AA, Volcik K et al (1996) Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 14:185–187CrossRefPubMedGoogle Scholar
  21. 21.
    Lakhani VT, You YN, Wells SA (2007) The multiple endocrine neoplasia syndromes. Annu Rev Med 58:253–265CrossRefPubMedGoogle Scholar
  22. 22.
    Allinen M, Huusko P, Mantyniemi S et al (2001) Mutation analysis of the CHK2 gene in families with hereditary breast cancer. Br J Cancer 85:209–212CrossRefPubMedGoogle Scholar
  23. 23.
    Rohlfs EM, Learning WG, Friedman KJ et al (1997) Direct detection of mutations in the breast and ovarian cancer susceptibility gene BRCA1 by PCR-mediated site-directed mutagenesis. Clin Chem 43:24–29PubMedGoogle Scholar
  24. 24.
    Csokay B, Tihomirova L, Stengrevics A et al (1999) Strong founder effects in BRCA1 mutation carrier breast cancer patients from Latvia. Hum Mutat 14:92CrossRefPubMedGoogle Scholar
  25. 25.
    Laitman Y, Kaufman B, Lahad EL et al (2007) Germline CHEK2 mutations in Jewish Ashkenazi women at high risk for breast cancer. Isr Med Assoc J 9:791–796PubMedGoogle Scholar
  26. 26.
    Cybulski C, Górski B, Huzarski T et al (2004) CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 75:1131–1135CrossRefPubMedGoogle Scholar
  27. 27.
    Huusko P, Pääkkönen K, Launonen V et al (1998) Evidence of founder mutations in Finnish BRCA1 and BRCA2 families. Am J Hum Genet 62:1544–1548CrossRefPubMedGoogle Scholar
  28. 28.
    Lee CH, Chung JH (2001) The hCds1 [Chk2]-FHA domain is essential for a chain of phosphorylation events on hCds1 that is induced by ionizing radiation. J Biol Chem 276:30537–30541CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Bella Kaufman
    • 1
  • Yael Laitman
    • 2
  • Jacek Gronwald
    • 4
  • Robert Winqvist
    • 5
  • Arvids Irmejs
    • 6
  • Jan Lubinski
    • 4
  • Katri Pylkäs
    • 5
  • Janis Gardovskis
    • 6
  • Edvins Miklasevics
    • 6
  • Eitan Friedman
    • 2
    • 3
    Email author
  1. 1.Institute of OncologyChaim Sheba Medical CenterTel-HashomerIsrael
  2. 2.The Susanne Levy Gertner Oncogenetics UnitThe Danek Gertner Institute of Human Genetics, Chaim Sheba Medical CenterTel-HashomerIsrael
  3. 3.Sackler Faculty of MedicineTel Aviv UniversityRamat AvivIsrael
  4. 4.Department of Genetics and PathologyInternational Hereditary Cancer Center, Pomeranian Medical UniversitySzczecinPoland
  5. 5.Laboratory of Cancer Genetics, Biocenter OuluOulu University Hospital, University of OuluOuluFinland
  6. 6.Hereditary Cancer InstituteRiga Stradins UniversityRigaLatvia

Personalised recommendations