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Inherited variation in the PARP1 gene and survival from melanoma

Davies, John R; Jewell, Rosalyn; Affleck, Paul; Anic, Gabriella M; Randerson-Moor, Juliette; Ozola, Aija; Egan, Kathleen M; Elliott, Faye; García-Casado, Zaida and Hansson, Johan, et al. (2014) In International Journal of Cancer 135(7). p.1625-1633
Abstract
We report the association of an inherited variant located upstream of the poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) gene (rs2249844), with survival in 11 BioGenoMEL melanoma cohorts. The gene encodes a protein involved in a number of cellular processes including single-strand DNA repair. Survival analysis was conducted for each cohort using proportional hazards regression adjusting for factors known to be associated with survival. Survival was measured as overall survival (OS) and, where available, melanoma-specific survival (MSS). Results were combined using random effects meta-analysis. Evidence for a role of the PARP1 protein in melanoma ulceration and survival was investigated by testing gene expression levels taken from... (More)
We report the association of an inherited variant located upstream of the poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) gene (rs2249844), with survival in 11 BioGenoMEL melanoma cohorts. The gene encodes a protein involved in a number of cellular processes including single-strand DNA repair. Survival analysis was conducted for each cohort using proportional hazards regression adjusting for factors known to be associated with survival. Survival was measured as overall survival (OS) and, where available, melanoma-specific survival (MSS). Results were combined using random effects meta-analysis. Evidence for a role of the PARP1 protein in melanoma ulceration and survival was investigated by testing gene expression levels taken from formalin-fixed paraffin-embedded tumors. A significant association was seen for inheritance of the rarer variant of PARP1, rs2249844 with OS (hazard ratio (HR) = 1.16 per allele, 95% confidence interval (CI) 1.04-1.28, p=0.005, eleven cohorts) and MSS (HR=1.20 per allele, 95% CI 1.01-1.39, p=0.03, eight cohorts). We report bioinformatic data supportive of a functional effect for rs2249844. Higher levels of PARP1 gene expression in tumors were shown to be associated with tumor ulceration and poorer OS. What's new? Although staging systems predict outcome fairly well for melanoma, survival still varies among individual patients. In this meta-analysis, the authors found that inheritance of a rare genetic variant of PARP1 was associated with improved survival of melanoma patients. Increased expression of PARP1 has been associated with poorer outcome, and depletion of PARP1 may reduce both melanoma growth and angiogenesis. The identification of this and other germline variants that affect survival may help to identify key biological pathways active in host/tumor interactions, which may lead to the discovery of new therapeutic targets for treating advanced melanoma. Epidemiology (Less)
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DNA, Neoplasm, Follow-Up Studies, Genetic Predisposition to Disease, Humans, Melanoma, Poly(ADP-ribose) Polymerases, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Prognosis, Quantitative Trait Loci, Retrospective Studies, Survival Rate, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
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International Journal of Cancer
volume
135
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7
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9 pages
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John Wiley & Sons
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  • wos:000340520800015
  • scopus:84904460022
ISSN
0020-7136
DOI
10.1002/ijc.28796http://dx.doi.org/10.1002/ijc.28796
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English
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1cb77357-aca8-4b11-9d70-6a2e46c89bc9 (old id 4656101)
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2014-10-01 07:26:25
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@article{1cb77357-aca8-4b11-9d70-6a2e46c89bc9,
  abstract     = {We report the association of an inherited variant located upstream of the poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) gene (rs2249844), with survival in 11 BioGenoMEL melanoma cohorts. The gene encodes a protein involved in a number of cellular processes including single-strand DNA repair. Survival analysis was conducted for each cohort using proportional hazards regression adjusting for factors known to be associated with survival. Survival was measured as overall survival (OS) and, where available, melanoma-specific survival (MSS). Results were combined using random effects meta-analysis. Evidence for a role of the PARP1 protein in melanoma ulceration and survival was investigated by testing gene expression levels taken from formalin-fixed paraffin-embedded tumors. A significant association was seen for inheritance of the rarer variant of PARP1, rs2249844 with OS (hazard ratio (HR) = 1.16 per allele, 95% confidence interval (CI) 1.04-1.28, p=0.005, eleven cohorts) and MSS (HR=1.20 per allele, 95% CI 1.01-1.39, p=0.03, eight cohorts). We report bioinformatic data supportive of a functional effect for rs2249844. Higher levels of PARP1 gene expression in tumors were shown to be associated with tumor ulceration and poorer OS. What's new? Although staging systems predict outcome fairly well for melanoma, survival still varies among individual patients. In this meta-analysis, the authors found that inheritance of a rare genetic variant of PARP1 was associated with improved survival of melanoma patients. Increased expression of PARP1 has been associated with poorer outcome, and depletion of PARP1 may reduce both melanoma growth and angiogenesis. The identification of this and other germline variants that affect survival may help to identify key biological pathways active in host/tumor interactions, which may lead to the discovery of new therapeutic targets for treating advanced melanoma. Epidemiology},
  author       = {Davies, John R and Jewell, Rosalyn and Affleck, Paul and Anic, Gabriella M and Randerson-Moor, Juliette and Ozola, Aija and Egan, Kathleen M and Elliott, Faye and García-Casado, Zaida and Hansson, Johan and Harland, Mark and Höiom, Veronica and Jian, Guan and Jönsson, Göran and Kumar, Rajiv and Nagore, Eduardo and Wendt, Judith and Olsson, Håkan and Park, Jong Y and Patel, Poulam and Pjanova, Dace and Puig, Susana and Schadendorf, Dirk and Sivaramakrishna Rachakonda, P and Snowden, Helen and Stratigos, Alexander J and Bafaloukos, Dimitrios and Ogbah, Zighereda and Sucker, Antje and Van den Oord, Joost J and Van Doorn, Remco and Walker, Christy and Okamoto, Ichiro and Wolter, Pascal and Barrett, Jennifer H and Timothy Bishop, D and Newton-Bishop, Julia},
  issn         = {0020-7136},
  keyword      = {DNA, Neoplasm,Follow-Up Studies,Genetic Predisposition to Disease,Humans,Melanoma,Poly(ADP-ribose) Polymerases,Polymerase Chain Reaction,Polymorphism, Single Nucleotide,Prognosis,Quantitative Trait Loci,Retrospective Studies,Survival Rate,Journal Article,Research Support, N.I.H., Extramural,Research Support, Non-U.S. Gov't},
  language     = {eng},
  month        = {10},
  number       = {7},
  pages        = {1625--1633},
  publisher    = {John Wiley & Sons},
  series       = {International Journal of Cancer},
  title        = {Inherited variation in the PARP1 gene and survival from melanoma},
  url          = {http://dx.doi.org/10.1002/ijc.28796http://dx.doi.org/10.1002/ijc.28796},
  volume       = {135},
  year         = {2014},
}