A large germline deletion in the Chek2 kinase gene is associated with an increased risk of prostate cancer

Cybulski, Cezary; Wokołorczyk, Dominika; Huzarski, Tomasz; Byrski, Tomasz; Gronwald, Jacek; Górski, Bohdan; Dębniak, Tadeusz; Masojć, Bartłomiej; Jakubowska, Anna; Gliniewicz, Bartłomiej; Sikorski, Andrzej; Stawicka, Małgorzata; Godlewski, Dariusz; Kwias, Zbigniew; Antczak, Andrzej; Krajka, K; Lauer, Wojciech; Sosnowski, Marek; Sikorska-Radek, Paulina; Bar, Krzysztof; Klijer, Robert; Zdrojowy, Romuald; Małkiewicz, Bartosz; Borkowski, Andrzej; Borkowski, Tomasz; Szwiec, Marek; Narod, Steven A.; Lubiński, Jan

doi:10.1136/jmg.2006.044974

Cited by 108 publications

(113 citation statements)

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“…Analogous to the current HOXB13 mutation, CHEK2 mutation frequencies in prostate cancer were significantly higher in populations from Northern and Eastern European countries as compared with North American populations, reflecting population-specific differences (42)(43)(44). CHEK2 is also a known breast cancer risk gene, and the frequency of 1100delC among patients with breast cancer varies similarly between European and North American populations (45,46).…”

Section: Discussionmentioning

confidence: 99%

HOXB13 G84E Mutation in Finland: Population-Based Analysis of Prostate, Breast, and Colorectal Cancer Risk

Laitinen

Wahlfors

Saaristo

et al. 2013

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: A recently identified germline mutation G84E in HOXB13 was shown to increase the risk of prostate cancer. In a family-based analysis by The International Consortium for Prostate Cancer Genetics (ICPCG), the G84E mutation was most prevalent in families from the Nordic countries of Finland (22.4%) and Sweden (8.2%).Methods: To further investigate the importance of G84E in the Finns, we determined its frequency in more than 4,000 prostate cancer cases and 5,000 controls. In addition, 986 breast cancer and 442 colorectal cancer (CRC) cases were studied. Genotyping was conducted using TaqMan, MassARRAY iPLEX, and sequencing. Statistical analyses were conducted using Fisher exact test, and overall survival was analyzed using Cox modeling.Results: The frequency of the G84E mutation was significantly higher among patients with prostate cancer and highest among patients with a family history of the disease, hereditary prostate cancer [8.4% vs. 1.0% in controls; OR 8.8; 95% confidence interval (CI), 4.9-15.7]. The mutation contributed significantly to younger age ( 55 years) at onset and high prostate-specific antigen (PSA; !20 ng/mL) at diagnosis. An association with increased prostate cancer risk in patients with prior benign prostate hyperplasia (BPH) diagnosis was also revealed. No statistically significant evidence for a contribution in CRC risk was detected, but a suggestive role for the mutation was observed in familial BRCA1/2-negative breast cancer.Conclusions: These findings confirm an increased cancer risk associated with the G84E mutation in the Finnish population, particularly for early-onset prostate cancer and cases with substantially elevated PSA.Impact: This study confirms the overall importance of the HOXB13 G84E mutation in prostate cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 22(3); 452-60. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 99%

HOXB13 G84E Mutation in Finland: Population-Based Analysis of Prostate, Breast, and Colorectal Cancer Risk

Laitinen

Wahlfors

Saaristo

et al. 2013

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Three founder mutations 1100delC, I157T, and 1422delT were first identified in Li-Fraumeni syndrome patients [25] but 1422delT is a polymorphism in a non-processed Psuedogene [26]. Other CHK2 mutations like S428F, IVS2 +IG > 2 and 5395delC have also been reported in different studies [27]- [30]. CHK2110delC is characterized by deletion of a single cystein at position 1100 located just at the beginning of exon 10 in the serine/threonine kinase domain and resulting in a frame shift mutation and an introduction of a stop codon after the 380 amino acid [25].…”

Section: Introductionmentioning

confidence: 99%

CHK21100delC, I157T, IVS2 +IG > A, BRCA1 and BRCA2 Mutation Analysis in JF305: A Pancreatic Cancer Cell Line

Ndawula¹,

Yang²,

Gong³

et al. 2014

JBM

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JF305 is a highly prolific pancreatic cancer cell line that originated from a Chinese patient. The cell line bears a functional HR double strand DNA repair mechanism but very responsive to PARP treatment a phenomenon clearly suggesting presence of an anomaly in the mechanism. Brca1, Brca2 and CHK2 proteins are very important constituents of the HR mechanism whose respective gene coding mutations are strongly associated with several cancers and are widely exploited in anticancer chemotherapy. In this current study, the BRCA1, BRCA2 gene mutation status in JF305 was determined together with the presence of 3 widely reported cancer linked CHK2 founder mutations (1100delC, I157T, IVS2 +IG > A). CHK21100delC genotype was determined using allele specific PCR, while the PCR-RFLP assay was used for I157T, IVS2 +IG > A analysis. PCR and direct sequencing were used for assessing the BRCA1 and BRCA2 gene. Results revealed that JF305 is CHK21100delC heterozygous mutant, CHK2I157T and CHK2IVS2 +IG > A wild type. Furthermore, it was observed that JF305 lacked BRCA1 and BRCA2 gene mutations. The mutation status identification of CHK2 and BRCA1/2 in JF305 provides a major milestone towards elucidating the properties of the cell line which subsequently promises to be an excellent model for evaluating the role of parp inhibitors in pancreatic cancer chemotherapy most especially in the respective cancer cell lines without BRCA1 and BRCA2 gene mutations.

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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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A large germline deletion in the Chek2 kinase gene is associated with an increased risk of prostate cancer

Cited by 108 publications

References 19 publications

HOXB13 G84E Mutation in Finland: Population-Based Analysis of Prostate, Breast, and Colorectal Cancer Risk

HOXB13 G84E Mutation in Finland: Population-Based Analysis of Prostate, Breast, and Colorectal Cancer Risk

CHK21100delC, I157T, IVS2 +IG > A, BRCA1 and BRCA2 Mutation Analysis in JF305: A Pancreatic Cancer Cell Line

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

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A large germline deletion in the Chek2 kinase gene is associated with an increased risk of prostate cancer

Cited by 108 publications

References 19 publications

HOXB13 G84E Mutation in Finland: Population-Based Analysis of Prostate, Breast, and Colorectal Cancer Risk

HOXB13 G84E Mutation in Finland: Population-Based Analysis of Prostate, Breast, and Colorectal Cancer Risk

CHK21100delC, I157T, IVS2 +IG &gt; A, BRCA1 and BRCA2 Mutation Analysis in JF305: A Pancreatic Cancer Cell Line

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

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CHK21100delC, I157T, IVS2 +IG > A, BRCA1 and BRCA2 Mutation Analysis in JF305: A Pancreatic Cancer Cell Line