Background Checkpoint kinase 2 (CHEK2) averts cancer development by promoting cell cycle arrest and activating DNA repair in genetically damaged cells. Previous investigation has established a role for the CHEK2 gene in breast cancer aetiology, but studies have largely been limited to the rare 1100delC mutation. Whether common polymorphisms in this gene influence breast cancer risk remains unknown. In this study, we aimed to assess the importance of common CHEK2 variants on population risk for breast cancer by capturing the majority of diversity in the gene using haplotype tagging single nucleotide polymorphisms (tagSNPs). Methods and Findings We analyzed 14 common SNPs spanning 52 kilobases (kb) of the CHEK2 gene in 92 Swedish women. Coverage evaluation indicated that these typed SNPs would efficiently convey association signal also from untyped SNPs in the same region. Six of the 14 SNPs predicted well both the haplotypic and single SNP variations within CHEK2. We genotyped these six tagSNPs in 1,577 postmenopausal breast cancer cases and 1,513 population controls, but found no convincing association between any common CHEK2 haplotype and breast cancer risk. The 1100delC mutation was rare in our Swedish population—0.7% in cases and 0.4% in controls—with a corresponding odds ratio for carriers versus noncarriers of 2.26 (95% confidence interval, 0.99–5.15). Estimates of the population frequency and the odds ratio of 1100delC indicate that our sample is representative of a Northern European population. Conclusions Notwithstanding the involvement of the CHEK2 gene in breast cancer aetiology, we show that common polymorphisms do not influence postmenopausal breast cancer risk.
References
[1]
Bray F, McCarron P, Parkin DM (2004) The changing global patterns of female breast cancer incidence and mortality. Breast Cancer Res 6: 229–239.
[2]
Peto J, Mack TM (2000) High constant incidence in twins and other relatives of women with breast cancer. Nat Genet 26: 411–414.
[3]
Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, et al. (2000) Environmental and heritable factors in the causation of cancer—Analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343: 78–85.
[4]
Antoniou AC, Pharoah PD, McMullan G, Day NE, Stratton MR, et al. (2002) A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer 86: 76–83.
[5]
Matsuoka S, Rotman G, Ogawa A, Shiloh Y, Tamai K, et al. (2000) Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proc Natl Acad Sci U S A 97: 10389–10394.
[6]
Shieh SY, Ahn J, Tamai K, Taya Y, Prives C (2000) The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev 14: 289–300.
[7]
Zeng Y, Forbes KC, Wu Z, Moreno S, Piwnica-Worms H, et al. (1998) Replication checkpoint requires phosphorylation of the phosphatase Cdc25 by Cds1 or Chk1. Nature 395: 507–510.
[8]
Lee JS, Collins KM, Brown AL, Lee CH, Chung JH (2000) hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 404: 201–204.
[9]
Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, et al. (2005) DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434: 864–870.
[10]
Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, et al. (2005) Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434: 907–913.
[11]
Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, et al. (2002) Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31: 55–59.
[12]
Vahteristo P, Bartkova J, Eerola H, Syrjakoski K, Ojala S, et al. (2002) A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet 71: 432–438.
[13]
Bell DW, Varley JM, Szydlo TE, Kang DH, Wahrer DC, et al. (1999) Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 286: 2528–2531.
Cybulski C, Gorski B, Huzarski T, Masojc B, Mierzejewski M, et al. (2004) CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 75: 1131–1135.
[16]
Friedrichsen DM, Malone KE, Doody DR, Daling JR, Ostrander EA (2004) Frequency of CHEK2 mutations in a population based, case-control study of breast cancer in young women. Breast Cancer Res 6: R629–635.
[17]
Mateus Pereira LH, Sigurdson AJ, Doody MM, Pineda MA, Alexander BH, et al. (2004) CHEK2:1100delC and female breast cancer in the United States. Int J Cancer 112: 541–543.
[18]
Caligo MA, Agata S, Aceto G, Crucianelli R, Manoukian S, et al. (2004) The CHEK2 c.1100delC mutation plays an irrelevant role in breast cancer predisposition in Italy. Hum Mutat 24: 100–101.
[19]
Osorio A, Rodriguez-Lopez R, Diez O, de la Hoya M, Ignacio Martinez J, et al. (2004) The breast cancer low-penetrance allele 1100delC in the CHEK2 gene is not present in Spanish familial breast cancer population. Int J Cancer 108: 54–56.
[20]
Huzarski T, Cybulski C, Domagala W, Gronwald J, Byrski T, et al. (2005) Pathology of breast cancer in women with constitutional CHEK2 mutations. Breast Cancer Res Treat 90: 187–189.
[21]
Offit K, Pierce H, Kirchhoff T, Kolachana P, Rapaport B, et al. (2003) Frequency of CHEK2*1100delC in New York breast cancer cases and controls. BMC Med Genet 4: 1.
[22]
de Jong MM, Nolte IM, Te Meerman GJ, van der Graaf WT, Oosterom E, et al. (2005) No increased susceptibility to breast cancer from combined CHEK2 1100delC genotype and the HLA class III region risk factors. Eur J Cancer 41: 1819–1823.
[23]
Gorski B, Cybulski C, Huzarski T, Byrski T, Gronwald J, et al. (2005) Breast cancer predisposing alleles in Poland. Breast Cancer Res Treat 92: 19–24.
[24]
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: 1175–1182.
[25]
Johnson N, Fletcher O, Naceur-Lombardelli C, dos Santos Silva I, Ashworth A, et al. (2005) Interaction between CHEK2*1100delC and other low-penetrance breast-cancer susceptibility genes: A familial study. Lancet 366: 1554–1557.
[26]
Bogdanova N, Enbetaen-Dubrowinskaja N, Feshchenko S, Lazjuk GI, Rogov YI, et al. (2005) Association of two mutations in the CHEK2 gene with breast cancer. Int J Cancer 116: 263–266.
[27]
Kilpivaara O, Vahteristo P, Falck J, Syrjakoski K, Eerola H, et al. (2004) CHEK2 variant I157T may be associated with increased breast cancer risk. Int J Cancer 111: 543–547.
[28]
Dufault MR, Betz B, Wappenschmidt B, Hofmann W, Bandick K, et al. (2004) Limited relevance of the CHEK2 gene in hereditary breast cancer. Int J Cancer 110: 320–325.
[29]
Schutte M, Seal S, Barfoot R, Meijers-Heijboer H, Wasielewski M, et al. (2003) Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility. Am J Hum Genet 72: 1023–1028.
[30]
Kuschel B, Auranen A, Gregory CS, Day NE, Easton DF, et al. (2003) Common polymorphisms in checkpoint kinase 2 are not associated with breast cancer risk. Cancer Epidemiol Biomarkers Prev 12: 809–812.
[31]
Magnusson C, Baron JA, Correia N, Bergstrom R, Adami HO, et al. (1999) Breast-cancer risk following long-term oestrogen- and oestrogen-progestin-replacement therapy. Int J Cancer 81: 339–344.
[32]
Magnusson C, Colditz G, Rosner B, Bergstrom R, Persson I (1998) Association of family history and other risk factors with breast cancer risk (Sweden). Cancer Causes Control 9: 259–267.
[33]
Magnusson CM, Persson IR, Baron JA, Ekbom A, Bergstrom R, et al. (1999) The role of reproductive factors and use of oral contraceptives in the aetiology of breast cancer in women aged 50 to 74 years. Int J Cancer 80: 231–236.
[34]
Moradi T, Nyren O, Zack M, Magnusson C, Persson I, et al. (2000) Breast cancer risk and lifetime leisure-time and occupational physical activity (Sweden). Cancer Causes Control 11: 523–531.
[35]
Terry P, Wolk A, Persson I, Magnusson C (2001) Brassica vegetables and breast cancer risk. JAMA 285: 2975–2977.
[36]
Isola J, DeVries S, Chu L, Ghazvini S, Waldman F (1994) Analysis of changes in DNA sequence copy number by comparative genomic hybridization in archival paraffin-embedded tumor samples. Am J Pathol 145: 1301–1308.
[37]
Zhao JH, Curtis D, Sham PC (2000) Model-free analysis and permutation tests for allelic associations. Hum Hered 50: 133–139.
[38]
Qin ZS, Niu T, Liu JS (2002) Partition-ligation-expectation-maximizat？ionalgorithm for haplotype inference with single-nucleotide polymorphisms. Am J Hum Genet 71: 1242–1247.
[39]
Stram DO, Haiman CA, Hirschhorn JN, Altshuler D, Kolonel LN, et al. (2003) Choosing haplotype-tagging SNPS based on unphased genotype data using a preliminary sample of unrelated subjects with an example from the Multiethnic Cohort Study. Hum Hered 55: 27–36.
[40]
Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, et al. (2002) The structure of haplotype blocks in the human genome. Science 296: 2225–2229.
[41]
Weale ME, Depondt C, Macdonald SJ, Smith A, Lai PS, et al. (2003) Selection and evaluation of tagging SNPs in the neuronal-sodium-channel gene SCN1A: Implications for linkage-disequilibrium gene mapping. Am J Hum Genet 73: 551–565.
[42]
Chapman JM, Cooper JD, Todd JA, Clayton DG (2003) Detecting disease associations due to linkage disequilibrium using haplotype tags: A class of tests and the determinants of statistical power. Hum Hered 56: 18–31.
[43]
Iles MM (2006) Obtaining unbiased estimates of tagging SNP performance. Ann Hum Genet 70: 254–261.
[44]
Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA (2002) Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 70: 425–434.
[45]
Hernan MA, Hernandez-Diaz S, Werler MM, Mitchell AA (2002) Causal knowledge as a prerequisite for confounding evaluation: An application to birth defects epidemiology. Am J Epidemiol 155: 176–184.
[46]
Molitor J, Marjoram P, Thomas D (2003) Fine-scale mapping of disease genes with multiple mutations via spatial clustering techniques. Am J Hum Genet 73: 1368–1384.
[47]
Beral V (2003) Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362: 419–427.
[48]
Kelsey JL, Gammon MD, John EM (1993) Reproductive factors and breast cancer. Epidemiol Rev 15: 36–47.
[49]
Sodha N, Williams R, Mangion J, Bullock SL, Yuille MR, et al. (2000) Screening hCHK2 for mutations. Science 289: 359.
[50]
Iles MM (2005) The effect of SNP marker density on the efficacy of haplotype tagging SNPs—a warning. Ann Hum Genet 69: 209–215.
[51]
Jekimovs CR, Chen X, Arnold J, Gatei M, Richard DJ, et al. (2005) Low frequency of CHEK2 1100delC allele in Australian multiple-case breast cancer families: Functional analysis in heterozygous individuals. Br J Cancer 92: 784–790.
[52]
Ahn J, Urist M, Prives C (2004) The Chk2 protein kinase. DNA Repair (Amst) 3: 1039–1047.
