Aberrations of the Chk2 tumour suppressor in advanced urinary bladder cancer

Bártková, Jiřina; Guldberg, Per; Grønbæk, Kirsten; Koed, Karen; Primdahl, Hanne; Møller, Klaus; Lukáš, Jiří; Ørntoft, Torben F.; Bártek, Jiří

doi:10.1038/sj.onc.1207878

Cited by 41 publications

(35 citation statements)

References 46 publications

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“…The reliability of the ligation assay was confirmed by re-analysis of 248 DNA samples from WECARE Study participants using denaturing gradient gel electrophoresis (DGGE), as described previously (Bartkova et al, 2004). We found complete concordance between the results obtained with these two methods (3 out of 248 samples screened were positive for mutations).…”

Section: Genotyping Of Chek2*1100delcsupporting

confidence: 69%

Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study

et al. 2008

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The protein encoded by the CHEK2 gene is involved in cellular repair of DNA damage. The truncating mutation, CHEK2*1100delC, seems to increase the risk for breast cancer. We investigated whether the CHEK2*1100delC mutation carrier status increases the risk for asynchronous contralateral breast cancer (CBC) and whether it interacts with radiation therapy (RT) or chemotherapy in regard to CBC risk. The germline mutation frequency was assessed in 708 women with CBC and 1395 women with unilateral breast cancer (UBC) in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study whose first primary breast cancer was diagnosed before age 55 years and during 1985 -1999. Seven women with CBC (1.0%) and 10 women with UBC (0.7%) were CHEK2*1100delC variant carriers (rate ratio (RR) ¼ 1.8, 95% confidence interval (CI) ¼ 0.6 -5.4 for CBC vs UBC). Carriers who received RT for their first breast cancer, compared with non-carriers not treated with RT, had an RR of developing CBC of 2.6 (95% CI ¼ 0.8 -8.7). We found no significant associations between the CHEK2*1100delC mutation and CBC overall or among those treated with RT. However, the sampling variability was such that modest increases in risk could not be excluded. Nonetheless, because this is a rare mutation, it is unlikely to explain a major fraction of CBC in the population.

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Section: Genotyping Of Chek2*1100delcsupporting

confidence: 69%

Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study

et al. 2008

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“…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. 1,11,[12][13][14][15][16]19,21,24,25 Two previous reports suggest that individuals with mutations in the CHEK2 gene might be at increased risk of bladder cancer. 13,14 To confirm this hypothesis, we have genotyped 416 incident cases of bladder cancer and 3,313 controls for the 4 CHEK2 founder mutations present in the Polish population.…”

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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%

“…12 Activation of CHEK2 in response to DNA damage is a signal to downstream targets in the checkpoint control pathways that include p53, Cdc25A, Cdc25C, BRCA1, E2F1, Pml1, Plk3 and other substrates whose biological functions become modified resulting in cell cycle blockade, enhanced DNA repair or apoptosis. 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.…”

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confidence: 99%

“…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%

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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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53BP1 loss induces chemoresistance of colorectal cancer cells to 5-fluorouracil by inhibiting the ATM–CHK2–P53 pathway

Yao

Huang

Zheng

et al. 2016

J Cancer Res Clin Oncol

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Aberrations of the Chk2 tumour suppressor in advanced urinary bladder cancer

Cited by 41 publications

References 46 publications

Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study

Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study

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

53BP1 loss induces chemoresistance of colorectal cancer cells to 5-fluorouracil by inhibiting the ATM–CHK2–P53 pathway

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