Identification of a common polymorphism in the TopBP1 gene associated with hereditary susceptibility to breast and ovarian cancer

Karppinen, Sanna-Maria; Erkko, Hannele; Reini, Kaarina; Pospiech, Helmut; Heikkinen, Kaisa; Rapakko, Katrin; Syväoja, Juhani E.; Winqvist, Robert

doi:10.1016/j.ejca.2006.05.030

Cited by 35 publications

(35 citation statements)

References 31 publications

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“…To date, there is no evidence that these proteins are ubiquitinylation substrates of EDD. Others have identified topoisomerase IIb-binding protein, required for cell survival after DNA damage (Yamane et al, 2002) and associated with an increased risk of familial breast and ovarian cancer (Karppinen et al, 2006), as a ubiquitinylation target of EDD (Honda et al, 2002).…”

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confidence: 99%

The E3 ubiquitin ligase EDD is an adverse prognostic factor for serous epithelial ovarian cancer and modulates cisplatin resistance in vitro

et al. 2008

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Despite a high initial response rate to first-line platinum/paclitaxel chemotherapy, most women with epithelial ovarian cancer relapse with recurrent disease that becomes refractory to further cytotoxic treatment. We have previously shown that the E3 ubiquitin ligase, EDD, a regulator of DNA damage responses, is amplified and overexpressed in serous ovarian carcinoma. Given that DNA damage pathways are linked to platinum resistance, the aim of this study was to determine if EDD expression was associated with disease recurrence and platinum sensitivity in serous ovarian cancer. High nuclear EDD expression, as determined by immunohistochemistry in a cohort of 151 women with serous ovarian carcinoma, was associated with an approximately two-fold increased risk of disease recurrence and death in patients who initially responded to first-line chemotherapy, independently of disease stage and suboptimal debulking. Although EDD expression was not directly correlated with relative cisplatin sensitivity of ovarian cancer cell lines, sensitivity to cisplatin was partially restored in platinum-resistant A2780-cp70 ovarian cancer cells following siRNA-mediated knockdown of EDD expression. These results identify EDD as a new independent prognostic marker for outcome in serous ovarian cancer, and suggest that pathways involving EDD, including DNA damage responses, may represent new therapeutic targets for chemoresistant ovarian cancer.

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confidence: 99%

The E3 ubiquitin ligase EDD is an adverse prognostic factor for serous epithelial ovarian cancer and modulates cisplatin resistance in vitro

et al. 2008

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“…TopBP1 and BRCA1 are phosphorylated by ATM in response to DNA damage and DNA replication stress and they both colocalize with PCNA (proliferating cell nuclear antigen) at stalled replication forks (Makiniemi et al, 2001;Yamane et al, 2003). The localization patterns of TopBP1 and BRCA1 have similarities also during late mitosis, as well as in meiotic prophase I (Karppinen et al, 2006;Reini et al, 2004). Furthermore, the two proteins have been shown to possess overlapping functions in G2/M checkpoint regulation (Karppinen et al, 2006).…”

Section: Fig 2 Topbp1 Functional Domains and Sites Of Interacting Pmentioning

confidence: 99%

“…The localization patterns of TopBP1 and BRCA1 have similarities also during late mitosis, as well as in meiotic prophase I (Karppinen et al, 2006;Reini et al, 2004). Furthermore, the two proteins have been shown to possess overlapping functions in G2/M checkpoint regulation (Karppinen et al, 2006). Yamane et al (2003) demonstrated that a BRCA1-mutant or a TopBP1-reduced background results in only partial abrogation at G2/M checkpoint, whereas the combined TopBP1-reduced and BRCA-mutant background result in the nearly complete abrogation.…”

Section: Fig 2 Topbp1 Functional Domains and Sites Of Interacting Pmentioning

confidence: 99%

“…The carboxyl-terminal region of TopBP1 containing two BRCT domains shows considerable similarity to the corresponding part of BRCA1 (Going et al, 2007;Karppinen et al, 2006;Makiniemi et al, 2001;Morris et al, 2009;Yamane et al, 1997Yamane et al, , 2003. Apart from structural similarity TopBP1 shares many other common features with BRCA1.…”

Section: Fig 2 Topbp1 Functional Domains and Sites Of Interacting Pmentioning

confidence: 99%

“…TopBP1 knockout mouse exhibits early embryonic lethality at the peri-implantation stage and TopBP1 deficiency induces cellular senescence in primary cells (Bang et al, 2011;Jeon et al, 2011). TopBP1 gene comprising 28 exons is located on chromosome 3q22.1 and encodes a 1522 amino acid protein (180 kDa) (Karppinen et al, 2006;Xu & Leffak, 2010;Yan & Michael, 2009a,b). The structure of protein is characterized by the presence of interspersed throughout the whole molecule eight copies of the BRCT domain (C-terminal domain of BRCA1), originally identified as a tandemly repeated sequence motif in carboxyl-terminal region of BRCA1 (Fig.…”

Section: Structure Of Topbp1 and Its Similarity To Brca1mentioning

confidence: 99%

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TopBP1 in DNA Damage Response

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Interaction of polymorphisms in mitotic regulator genes with cigarette smoking and pancreatic cancer risk

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Mitotic regulator genes have been associated with several cancers, however little is known about their possible association with pancreatic cancer. Smoking and family history are the strongest risk factors for this highly fatal disease. The main purpose of this study was to determine if polymorphisms of mitotic regulator genes are associated with pancreatic cancer and whether they modify the association between cigarette smoking and pancreatic cancer risk. A population-based case-control study was conducted in Ontario with 455 pathology-confirmed pancreatic cancer cases and 893 controls. Cigarette smoking history was collected using questionnaires and DNA obtained from blood samples. Genotypes were determined by mass-spectrometry. Odds ratio estimates were obtained using multivariate logistic regression. Interactions between genetic variant and smoking were assessed using stratified analyses and the likelihood ratio statistic (significance P < 0.05). Variants of MCPH1, FYN, APC, PRKCA, NIN, TopBP1, RIPK1, and SNW1 were not independently associated with pancreatic cancer risk. A significant interaction was observed between pack-years and MCPH1-2550-C > T (P = 0.02). Compared to never smokers, individuals with 10–27 pack-years and MCPH1-2550-CC genotype were at increased risk for pancreatic cancer (MVOR = 2.49, 95% confidence interval [95% CI]: 1.55, 4.00) as were those with >27 pack-years and MCPH1-2550-TC genotype (MVOR = 2.42, 95% CI: 1.45, 4.05). A significant interaction was observed between smoking status and TopBP1-3257-A > G (P = 0.04) using a dominant model. Current smokers with the TopBP1-3257 A allele were at increased risk for pancreatic cancer (MVOR = 2.55, 95% CI: 1.77, 3.67). MCPH1-2550-C > T and TopBP1-3257-A > G modify the association between smoking and pancreatic cancer. These findings provide insights into the potential molecular mechanisms behind smoking-associated pancreatic cancer.

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Identification of a common polymorphism in the TopBP1 gene associated with hereditary susceptibility to breast and ovarian cancer

Cited by 35 publications

References 31 publications

The E3 ubiquitin ligase EDD is an adverse prognostic factor for serous epithelial ovarian cancer and modulates cisplatin resistance in vitro

The E3 ubiquitin ligase EDD is an adverse prognostic factor for serous epithelial ovarian cancer and modulates cisplatin resistance in vitro

TopBP1 in DNA Damage Response

Interaction of polymorphisms in mitotic regulator genes with cigarette smoking and pancreatic cancer risk

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