Germline CHEK2 mutations and colorectal cancer risk: different effects of a missense and truncating mutations?

Cybulski, Cezary; lstrok, Dominika Woko; orczyk,; lstrok, Józef K; adny,; Kurzwaski, Grzegorz; Suchy, Joanna; Grabowska, Ewa; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Górski, Bohdan; ecedil, Tadeusz D; bniak,; Narod, Steven A.; nacute, Jan Lubi; ski,

doi:10.1038/sj.ejhg.5201734

Cited by 65 publications

(60 citation statements)

References 32 publications

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“…The first 1050 colon cancer patients have been described in detail previously (Cybulski et al, 2007b). The study has since been extended to include more patients using the same methodology.…”

Section: Study Subjectsmentioning

confidence: 99%

“…For breast and prostate cancer, the truncating mutations are associated with higher penetrance than the missense mutation (Cybulski et al, 2007c). For colon cancer, only the missense variant I157T is associated with an elevated risk (Cybulski et al, 2007b). The odds ratios reported to be associated with truncating and missense mutations for breast, prostate and colon cancer in our most recent studies are presented in Table 1.…”

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confidence: 92%

“…CHEK2 mutations predispose men and women to a range of cancer types, including breast, prostate and colon (Cybulski et al, 2004b;Cybulski et al, 2007b). For breast and prostate cancer, the truncating mutations are associated with higher penetrance than the missense mutation (Cybulski et al, 2007c).…”

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confidence: 99%

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Cancer risks in first-degree relatives of CHEK2 mutation carriers: effects of mutation type and cancer site in proband

et al. 2009

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It is important to have accurate knowledge of the range of cancers associated with various CHEK2 mutations, and of the lifetime risks of cancer associated with each. We wished to establish the relationship between family history, mutation type and cancer risk in families with a CHEK2 mutation. We obtained a blood sample and pedigree information from 2012 unselected women with breast cancer, from 2007 men with prostate cancer and from 1934 patients with colon cancer, from hospitals throughout Poland. Genetic testing was carried out for four founder CHEK2 mutations on all 5953 specimens and 533 carriers were identified. We estimated the risk to age 75 for any cancer in the 2544 first-degree relatives to be 22.3%. After adjusting for mutation type, the risk of breast cancer was much higher among relatives of probands with breast cancer than among relatives of patients with prostate or colon cancer (HR ¼ 3.6; 95% CI ¼ 2.1 -6.2; P ¼ 0.0001). Similarly, the risk of prostate cancer was higher among relatives of probands with prostate cancer than among relatives of patients with breast or colon cancer (HR ¼ 4.4; 95% CI ¼ 2.2 -8.7; P ¼ 0.0001) and the risk of colon cancer was higher among relatives of probands with colon cancer than among relatives of patients with prostate or breast cancer (HR ¼ 4.2; 95% CI ¼ 2.4 -7.8; P ¼ 0.0001). These analyses suggest that the risk of cancer in a carrier of a CHEK2 mutation is dependent on the family history of cancer.

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confidence: 99%

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confidence: 92%

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Cancer risks in first-degree relatives of CHEK2 mutation carriers: effects of mutation type and cancer site in proband

et al. 2009

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“…Two primers pairs were used for genotyping of the large deletion of exon 9 and 10 in a multiplex-PCR reaction as described previously. 26,27 The first primer pair flanked the breakpoint site in intron 8 and the second primer pair flanked the breakpoint site in intron 10. In mutation-negative cases, only two PCR fragments of 379 and 522 bp were amplified from the wild type allele.…”

Section: Genotypingmentioning

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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“…In addition, the discovery of a mutation in such a moderatepenetrance gene may not provide a compelling explanation for the family history that may have prompted testing in the first place. Cancer penetrance associated with CHEK2 may be influenced by specific mutations (e.g., CHEK2 1100delC versus I157T), 6 as well as the associated family history. 7 Risks of other cancers, such as colon cancer, appear to be modestly elevated, but whether this should alter screening recommendations (including age at which to begin or frequency of screening) is unknown.…”

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confidence: 99%

Panel testing for inherited susceptibility to breast, ovarian, and colorectal cancer

Domchek

Nathanson

2014

Genetics in Medicine

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Germline CHEK2 mutations and colorectal cancer risk: different effects of a missense and truncating mutations?

Cited by 65 publications

References 32 publications

Cancer risks in first-degree relatives of CHEK2 mutation carriers: effects of mutation type and cancer site in proband

Cancer risks in first-degree relatives of CHEK2 mutation carriers: effects of mutation type and cancer site in proband

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

Panel testing for inherited susceptibility to breast, ovarian, and colorectal cancer

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