title: Inherited variation in the PARP1 gene and survival from melanoma.
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.
authors.affiliation: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: John R
authors.initials: JR
authors.lastname: Davies
authors.forename: Rosalyn
authors.initials: R
authors.lastname: Jewell
authors.forename: Paul
authors.initials: P
authors.lastname: Affleck
authors.forename: Gabriella M
authors.initials: GM
authors.lastname: Anic
authors.forename: Juliette
authors.initials: J
authors.lastname: Randerson-Moor
authors.forename: Aija
authors.initials: A
authors.lastname: Ozola
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Egan
authors.forename: Faye
authors.initials: F
authors.lastname: Elliott
authors.forename: Zaida
authors.initials: Z
authors.lastname: García-Casado
authors.forename: Johan
authors.initials: J
authors.lastname: Hansson
authors.forename: Mark
authors.initials: M
authors.lastname: Harland
authors.forename: Veronica
authors.initials: V
authors.lastname: Höiom
authors.forename: Guan
authors.initials: G
authors.lastname: Jian
authors.forename: Göran
authors.initials: G
authors.lastname: Jönsson
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.forename: Eduardo
authors.initials: E
authors.lastname: Nagore
authors.forename: Judith
authors.initials: J
authors.lastname: Wendt
authors.forename: Håkan
authors.initials: H
authors.lastname: Olsson
authors.forename: Jong Y
authors.initials: JY
authors.lastname: Park
authors.forename: Poulam
authors.initials: P
authors.lastname: Patel
authors.forename: Dace
authors.initials: D
authors.lastname: Pjanova
authors.forename: Susana
authors.initials: S
authors.lastname: Puig
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: P
authors.initials: P
authors.lastname: Sivaramakrishna Rachakonda
authors.forename: Helen
authors.initials: H
authors.lastname: Snowden
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Stratigos
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Bafaloukos
authors.forename: Zighereda
authors.initials: Z
authors.lastname: Ogbah
authors.forename: Antje
authors.initials: A
authors.lastname: Sucker
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Van den Oord
authors.forename: Remco
authors.initials: R
authors.lastname: Van Doorn
authors.forename: Christy
authors.initials: C
authors.lastname: Walker
authors.forename: Ichiro
authors.initials: I
authors.lastname: Okamoto
authors.forename: Pascal
authors.initials: P
authors.lastname: Wolter
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Barrett
authors.forename: D
authors.initials: D
authors.lastname: Timothy Bishop
authors.forename: Julia
authors.initials: J
authors.lastname: Newton-Bishop
mesh_terms: D004273:DNA, Neoplasm / Q000235:genetics; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000401:mortality*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D040641:Quantitative Trait Loci; D012189:Retrospective Studies; D015996:Survival Rate
chemical_list: D004273:DNA, Neoplasm; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: PARP1; bioinformatics; genetic determinants of survival; melanoma; random effects meta-analysis; survival