Inherited variation in the PARP1 gene and survival from melanoma

Research output: Contribution to journalArticle

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

Details

Authors
  • John R Davies
  • Rosalyn Jewell
  • Paul Affleck
  • Gabriella M Anic
  • Juliette Randerson-Moor
  • Aija Ozola
  • Kathleen M Egan
  • Faye Elliott
  • Zaida García-Casado
  • Johan Hansson
  • Mark Harland
  • Veronica Höiom
  • Guan Jian
  • Rajiv Kumar
  • Eduardo Nagore
  • Judith Wendt
  • Jong Y Park
  • Poulam Patel
  • Dace Pjanova
  • Susana Puig
  • Dirk Schadendorf
  • P Sivaramakrishna Rachakonda
  • Helen Snowden
  • Alexander J Stratigos
  • Dimitrios Bafaloukos
  • Zighereda Ogbah
  • Antje Sucker
  • Joost J Van den Oord
  • Remco Van Doorn
  • Christy Walker
  • Ichiro Okamoto
  • Pascal Wolter
  • Jennifer H Barrett
  • D Timothy Bishop
  • Julia Newton-Bishop
Organisations
External organisations
  • University of Leeds
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology

Keywords

  • 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
Original languageEnglish
Pages (from-to)1625-1633
Number of pages9
JournalInternational Journal of Cancer
Volume135
Issue number7
StatePublished - 2014 Oct 1
Peer-reviewedYes