Variants in CHEK2 Other than 1100delC Do Not Make a Major Contribution to Breast Cancer Susceptibility

Schutte, Mieke; Seal, Sheila; Barfoot, Rita; Meijers-Heijboer, Hanne; Wasielewski, Marijke; Evans, D. Gareth; Eccles, Diana; Meijers, Carel; Lohman, Frans P.; Klijn, Jan G.M.; Ouweland, Ans van den; Futreal, P. Andrew; Nathanson, Katherine L.; Weber, Barbara; Easton, Douglas F.; Stratton, Michael R.; Rahman, Nazneen

doi:10.1086/373965

Cited by 119 publications

(93 citation statements)

References 26 publications

(31 reference statements)

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“…[14][15][16] The reasons for the discrepancies between these results and ours may be heterogeneous and could be due to a smaller cohort size, 14 a very low frequency of the I157T allele 15 or a sampling bias toward multiplecase families who were negative for BRCA1 and BRCA2 gene mutations. 15,16 While our results clearly demonstrate a role for the CHEK2 mutation I157T in inherited breast cancer susceptibility, we have not detected a further increase in the frequency of this allele in familial breast cancer. Similarly, a study of Finnish breast cancer patients revealed some evidence for an association of FIGURE 1 -Identification and confirmation of the CHEK2 gene mutations IVS211G>A and I157T by screening of PCR products using restriction enzymes ScrFI and PstI (upper figure, S, size marker; P, heterozygous patient; C, wild-type control) and subsequent direct sequencing of PCR products from heterozygous patients (lower panel, sense strand with N designating the mutated position).…”

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confidence: 61%

Association of two mutations in the CHEK2 gene with breast cancer

Bogdanova

Enssen-Dubrowinskaja

Feshchenko³

et al. 2005

Intl Journal of Cancer

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The 1100delC mutation of the cell cycle checkpoint kinase 2 (CHEK2) gene confers an increased risk for breast cancer, but the clinical impact of other CHEK2 gene variants remains unclear. We determined the frequency of two functionally relevant CHEK2 gene mutations, I157T and IVS211G > A, in two large series of breast cancer cases and controls from two independent populations. Our first series consisted of a hospital-based cohort of 996 German breast cancer cases and 486 population controls, and the second series consisted of 424 breast cancer patients and 307 population controls from the Republic of Belarus. The missense substitution I157T was identified in 22⁄996 cases (2.2%) vs. 3⁄486 controls (0.6%; OR 5 3.6, 95% CI 1.1-12.2, p 5 0.044) in the German population and in 24⁄424 cases (5.7%) vs. 4⁄307 controls (1.3%; OR 5 4.5, 95% CI 1.6-13.2, p 5 0.005) in the Byelorussian cohorts. The splicing mutation IVS211G > A was infrequent in both populations, being observed in 3⁄996 German and 4⁄424 Byelorussian patients (0.3% and 0.9%, respectively) and in 1⁄486 German controls (0.2%; adjusted OR 5 4.0, 95% CI 0.5-30.8, p 5 0.273). Heterozygous CHEK2 mutation carriers tended to be diagnosed at an earlier age in both populations, but these differences did not reach statistical significance. Family history of breast cancer did not differ between carriers and noncarriers. Our data indicate that the I157T allele, and possibly the IVS211G > A allele, of the CHEK2 gene contribute to inherited breast cancer susceptibility. ' 2005 Wiley-Liss, Inc.Key words: breast cancer; CHEK2; Germany; Belarus Cell-cycle checkpoint kinase 2 (CHEK2) is a central mediator of cellular responses to DNA damage.1,2 Ionizing radiation activates the CHEK2 protein via ATM-mediated phosphorylation, 3,4 and activated CHEK2 kinase can phosphorylate several substrates, including Cdc25A, p53 and E2F1, which mediate cell cycle arrest and apoptosis.1,2,5 CHEK2 phosphorylation of the breast cancer susceptibility protein BRCA1 regulates DNA double-strand break repair, 6 and deletion of CHEK2 potentiates the incidence of mammary carcinomas in BRCA1 conditional mutant mice.7 A truncating variant of CHEK2, the 1100delC mutation, has been identified as a low-penetrance breast-cancer susceptibility allele. 8,9 Heterozygous 1100delC carriers have an approximately 2-fold increased risk for breast cancer.10 Furthermore, a potential association of the 1100delC mutation with colorectal and prostate cancers has been reported. 11-13The role of variants in CHEK2 other than 1100delC is less clear. Most studies have led to the conclusion that other CHEK2 mutations do not make a major contribution to breast cancer susceptibility.14-16 However, one more recent investigation suggests that the common I157T mutation may be associated with increased breast cancer risk. 17 Parallel work has provided evidence that the missense substitution I157T as well as the splicing mutation IVS211G>A may confer an elevated risk for prostate cancer. 13,18 To assess the role of these CHEK2 varia...

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confidence: 61%

Association of two mutations in the CHEK2 gene with breast cancer

Bogdanova

Enssen-Dubrowinskaja

Feshchenko³

et al. 2005

Intl Journal of Cancer

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“…It has a slightly higher frequency among patients with unselected prostate cancer than among control individuals and it is strongly associated with family history of the disease. However, according to the previous reports, the I157T allele does not make a significant contribution to breast cancer susceptibility (Allinen et al, 2001;Schutte et al, 2003). Therefore, the association with this allele is less conclusive.…”

Section: Discussionmentioning

confidence: 85%

CHEK2 variants associate with hereditary prostate cancer

et al. 2003

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Recently, variants in CHEK2 gene were shown to associate with sporadic prostate cancer in the USA. In the present study from Finland, we found that the frequency of 1100delC, a truncating variant that abrogates the kinase activity, was significantly elevated among 120 patients with hereditary prostate cancer (HPC) (four out of 120 (3.3%); odds ratio 8.24; 95% confidence interval 1.49 -45.54; P ¼ 0.02) compared to 480 population controls. Suggestive evidence of segregation between the 1100delC mutation and prostate cancer was seen in all positive families. In addition, I157T variant had significantly higher frequency among HPC patients (13 out of 120 (10.8%); odds ratio 2.12; 95% confidence interval 1.06 -4.27; P ¼ 0.04) than the frequency 5.4% seen in the population controls. The results suggest that CHEK2 variants are low-penetrance prostate cancer predisposition alleles that contribute significantly to familial clustering of prostate cancer at the population level.

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“…6,8,[12][13][14][15][16][17][18][19][20] CHEK2 is phosphorylated and regulated by the Ataxia Telangiectasia Mutated (ATM) kinase, another crucial mediator of cell cycle checkpoint control. 15,17 Cell cycle checkpoint control mechanisms are essential for the maintenance of genomic integrity but there appear to be differences in the efficiency of this process due to polymorphic variation, which have been suggested to contribute to oncogenesis.…”

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confidence: 99%

“…7,[12][13][14][15][16][17]19,21,22 The first mutations in CHEK2 which were reported in sporadic and hereditary cancers indicated that CHEK2 defects might explain the tumor-prone phenotype in families with Li-Fraumeni syndrome (LFS). 1,12,13,15,17,18,23 To date CHEK2 mutations have been found in subset of human breast carcinomas, testicular tumors and lymphomas. Germline CHEK2 mutations have been associated with an increased risk of breast, prostate, colon cancers, thyroid, kidney, low-grade ovarian cancers and lymphomas, but bladder cancer has not been studied extensively.…”

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confidence: 99%

Germline mutations in the CHEK2 kinase gene are associated with an increased risk of bladder cancer

Złowocka

Cybulski

Górski

et al. 2007

Intl Journal of Cancer

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Germline mutations in CHEK2 have been associated with a range of cancer types but little is known about disease risks conveyed by CHEK2 mutations outside of the context of breast and prostate cancer. To investigate whether CHEK2 mutations confer an increased risk of bladder cancer, we genotyped 416 unselected cases of bladder cancer and 3,313 controls from Poland for 4 founder alleles in the CHEK2 gene, each of which has been associated with an increased risk of cancer at other sites. A CHEK2 mutation (all variants combined) was found in 10.6% of the cancer cases and in 5.9% of the controls (OR 5 1.9; 95%CI 1.3-2.7; p 5 0.0003). We conclude that CHEK2 mutations increase the risk of bladder cancer in the population. ' 2007 Wiley-Liss, Inc.Key words: bladder cancer; CHEK2; CHK2 germline mutations; susceptibility Urothelial bladder cancer is the second most common tumor of the genitourinary tract and has the highest recurrence rate of any cancer. In Poland 3,500 new cases of bladder cancer are diagnosed annually. Bladder cancer develops more predominantly in males and increases significantly in incidence between the ages of 60 and 70 years in the life. The risk factors for developing bladder cancer are: cigarette smoking, exposure to aromatic amines, polycyclic aromatic hydrocarbons and infection with Schistosoma haematobium. [1][2][3][4] There is evidence that some bladder cancers are a result of a genetic predisposition to disease. Several studies have reported an association of bladder cancer with polymorphisms in xenobiotic metabolizing enzymes. The glutathione S Transferase M1 (GSTM1) null phenotype has been implicated with bladder cancer and polymorphisms in the N-acetyl transferase 2 (NAT2) gene that result in slow acetylation have also been linked to bladder cancer but only in association with tobacco smoke exposure. 5 One of the most frequently disrupted chromosomes associated with bladder cancer development is chromosome 17. 6 Approximately 40% of bladder tumors are characterized by loss of heterozygosity (LOH) on the short arm of chromosome 17. One of the genes located in this region of loss is the p53 tumor suppressor gene. The p53 gene plays an important role in DNA repair as it encodes a 53Kd phosphoprotein, which is involved in the control and holding of cells in G1-S phase of the cell cycle. 6 The p53 protein interacts with the product of another tumor suppressor gene, CHEK2. 7,8 The CHEK2 gene (cell cycle checkpoint kinase2) is located on the long arm of chromosome 22. It is homologous to the protein kinases Cds1 and Rad53 found in Schizosaccharomyces pombe and Saccharomyces cerevisiae, respectively. 9 The Cds1/Rad53 proteins have been shown to be required for the response to various forms of DNA damage as has as CHEK2, which in mammalian cells is associated with an arrest of the cell cycle at G2 in response to DNA damage 10,11 such as DNA double strand breaks, the most lethal type of DNA damage.The causes of double stranded DNA breaks include exposure to environmental mutagens such as genotoxic c...

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Variants in CHEK2 Other than 1100delC Do Not Make a Major Contribution to Breast Cancer Susceptibility

Cited by 119 publications

References 26 publications

Association of two mutations in the CHEK2 gene with breast cancer

Association of two mutations in the CHEK2 gene with breast cancer

CHEK2 variants associate with hereditary prostate cancer

Germline mutations in the CHEK2 kinase gene are associated with an increased risk of bladder cancer

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