Original article| Volume 208, ISSUE 4, P129-134, April 2015

CHEK2 c.1100delC allele is rarely identified in Greek breast cancer cases

      The CHEK2 gene encodes a protein kinase that plays a crucial role in maintenance of genomic integrity and the DNA repair mechanism. CHEK2 germline mutations are associated with increased risk of breast cancer and other malignancies. From a clinical perspective, the most significant mutation identified is the c.1100delC mutation, which is associated with an approximately 25% lifetime breast cancer risk. The distribution of this mutation shows wide geographical variation; it is more prevalent in the Northern European countries and less common, or even absent, in Southern Europe. In order to estimate the frequency of the CHEK2 c.1100delC mutation in Greek breast cancer patients, we genotyped 2,449 patients (2,408 females and 41 males), which was the largest series ever tested for c.1100delC. The mean age of female and male breast cancer diagnosis was 49 and 59 years, respectively. All patients had previously tested negative for the Greek BRCA1 founder and recurrent mutations. The CHEK2 c.1100delC mutation was detected in 0.16% (4 of 2,408) of females, all of whom were diagnosed with breast cancer before the age of 50 years. Only one c.1100delC carrier was reported with breast cancer family history. The present study indicates that the CHEK2 c.1100delC mutation does not contribute substantially to hereditary breast cancer in patients of Greek descent.


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        • Ferlay J.
        • Parkin D.M.
        • Steliarova-Foucher E.
        Estimates of cancer incidence and mortality in Europe in 2008.
        Eur J Cancer. 2010; 46: 765-781
        • Lalloo F.
        • Evans D.G.
        Familial breast cancer.
        Clin Genet. 2012; 82: 105-114
        • Rahman N.
        • Stratton M.R.
        The genetics of breast cancer susceptibility.
        Annu Rev Genet. 1998; 32: 95-121
        • Claus E.B.
        • Risch N.
        • Thompson W.D.
        Genetic analysis of breast cancer in the cancer and steroid hormone study.
        Am J Hum Genet. 1991; 48: 232-242
        • Newman B.
        • Austin M.A.
        • Lee M.
        • et al.
        Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families.
        Proc Natl Acad Sci U S A. 1988; 85: 3044-3048
        • Hall J.M.
        • Lee M.K.
        • Newman B.
        • et al.
        Linkage of early-onset familial breast cancer to chromosome 17q21.
        Science. 1990; 250: 1684-1689
        • Miki Y.
        • Swensen J.
        • Shattuck-Eidens D.
        • et al.
        A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.
        Science. 1994; 266: 66-71
        • McClellan J.
        • King M.C.
        Genetic heterogeneity in human disease.
        Cell. 2010; 141: 210-217
        • Walsh T.
        • King M.C.
        Ten genes for inherited breast cancer.
        Cancer Cell. 2007; 11: 103-105
        • Walsh T.
        • Casadei S.
        • Lee M.K.
        • et al.
        Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.
        Proc Natl Acad Sci U S A. 2011; 108: 18032-18037
        • Meijers-Heijboer H.
        • van den Ouweland A.
        • Klijn J.
        • et al.
        Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations.
        Nat Genet. 2002; 31: 55-59
        • Antoni L.
        • Sodha N.
        • Collins I.
        • et al.
        CHK2 kinase: cancer susceptibility and cancer therapy - two sides of the same coin?.
        Nat Rev Cancer. 2007; 7: 925-936
        • Bartek J.
        • Falck J.
        • Lukas J.
        CHK2 kinase–a busy messenger.
        Nat Rev Mol Cell Biol. 2001; 2: 877-886
        • Bell D.W.
        • Varley J.M.
        • Szydlo T.E.
        • et al.
        Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome.
        Science. 1999; 286: 2528-2531
        • Bahassi el M.
        • Robbins S.B.
        • Yin M.
        • et al.
        Mice with the CHEK2*1100delC SNP are predisposed to cancer with a strong gender bias.
        Proc Natl Acad Sci U S A. 2009; 106: 17111-17116
        • Nguyen-Dumont T.
        • Jordheim L.P.
        • Michelon J.
        • et al.
        Detecting differential allelic expression using high-resolution melting curve analysis: application to the breast cancer susceptibility gene CHEK2.
        BMC Med Genomics. 2011; 4: 39
        • Nagel J.H.
        • Peeters J.K.
        • Smid M.
        • et al.
        Gene expression profiling assigns CHEK2 1100delC breast cancers to the luminal intrinsic subtypes.
        Breast Cancer Res Treat. 2012; 132: 439-448
        • Anczuków O.
        • Ware M.D.
        • Buisson M.
        • et al.
        Does the nonsense-mediated mRNA decay mechanism prevent the synthesis of truncated BRCA1, CHK2, and p53 proteins?.
        Hum Mutat. 2008; 29: 65-73
        • Vahteristo P.
        • Bartkova J.
        • Eerola H.
        • et al.
        A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer.
        Am J Hum Genet. 2002; 71: 432-438
        • de Bock G.H.
        • Schutte M.
        • Krol-Warmerdam E.M.
        • et al.
        Tumour characteristics and prognosis of breast cancer patients carrying the germline CHEK2*1100delC variant.
        J Med Genet. 2004; 41: 731-735
        • Oldenburg R.A.
        • Kroeze-Jansema K.
        • Kraan J.
        • et al.
        The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families.
        Cancer Res. 2003; 63: 8153-8157
        • Schmidt M.K.
        • Tollenaar R.A.
        • de Kemp S.R.
        • et al.
        Breast cancer survival and tumor characteristics in premenopausal women carrying the CHEK2*1100delC germline mutation.
        J Clin Oncol. 2007; 25: 64-69
        • Osorio A.
        • Rodriguez-López R.
        • Diez O.
        • et al.
        The breast cancer low-penetrance allele 1100delC in the CHEK2 gene is not present in Spanish familial breast cancer population.
        Int J Cancer. 2004; 108: 54-56
        • Caligo M.A.
        • Agata S.
        • Aceto G.
        • et al.
        The CHEK2 c.1100delC mutation plays an irrelevant role in breast cancer predisposition in Italy.
        Hum Mutat. 2004; 24: 100-101
        • Miller S.A.
        • Dykes D.D.
        • Polesky H.F.
        A simple salting out procedure for extracting DNA from human nucleated cells.
        Nucleic Acids Res. 1988; 16: 1215
        • Krivokuca A.
        • Dobricic J.
        • Brankovic-Magic M.
        CHEK2 1100delC and Del5395bp mutations in BRCA-negative individuals from Serbian hereditary breast and ovarian cancer families.
        J BUON. 2013; 18: 594-600
        • CHEK2 Breast Cancer Case-Control Consortium
        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. 2004; 74: 1175-1182
        • Weischer M.
        • Bojesen S.E.
        • Tybjaerg-Hansen A.
        • et al.
        Increased risk of breast cancer associated with CHEK2*1100delC.
        J Clin Oncol. 2007; 25: 57-63
        • Rashid M.U.
        • Jakubowska A.
        • Justenhoven C.
        • et al.
        German populations with infrequent CHEK2*1100delC and minor associations with early-onset and familial breast cancer.
        Eur J Cancer. 2005; 41: 2896-2903
        • Cybulski C.
        • Wokolorczyk D.
        • Huzarski T.
        • et al.
        A deletion in CHEK2 of 5,395 bp predisposes to breast cancer in Poland.
        Breast Cancer Res Treat. 2007; 102: 119-122
        • Kilpivaara O.
        • Bartkova J.
        • Eerola H.
        • et al.
        Correlation of CHEK2 protein expression and c.1100delC mutation status with tumor characteristics among unselected breast cancer patients.
        Int J Cancer. 2005; 113: 575-580
        • Kriege M.
        • Hollestelle A.
        • Jager A.
        • et al.
        Survival and contralateral breast cancer in CHEK2 1100delC breast cancer patients: impact of adjuvant chemotherapy.
        Br J Cancer. 2014; 111: 1004-1013
        • Kleibl Z.
        • Novotny J.
        • Bezdickova D.
        • et al.
        The CHEK2 c.1100delC germline mutation rarely contributes to breast cancer development in the Czech Republic.
        Breast Cancer Res Treat. 2005; 90: 165-167
        • Zhang S.
        • Phelan C.M.
        • Zhang P.
        • et al.
        Frequency of the CHEK2 1100delC mutation among women with breast cancer: an international study.
        Cancer Res. 2008; 68: 2154-2157
        • Offit K.
        • Pierce H.
        • Kirchhoff T.
        • et al.
        Frequency of CHEK2*1100delC in New York breast cancer cases and controls.
        BMC Med Genet. 2003; 4: 1
        • Iniesta M.D.
        • Gorin M.A.
        • Chien L.C.
        • et al.
        Absence of CHEK2*1100delC mutation in families with hereditary breast cancer in North America.
        Cancer Genet Cytogenet. 2010; 202: 136-140
        • Jekimovs C.R.
        • Chen X.
        • Arnold J.
        • et al.
        Low frequency of CHEK2 1100delC allele in Australian multiple-case breast cancer families: functional analysis in heterozygous individuals.
        Br J Cancer. 2005; 92: 784-790