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Inherited variation in the PARP1 gene and survival from melanoma |
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| 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 Göran Jönsson Rajiv Kumar Eduardo Nagore Judith Wendt Håkan Olsson 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 |
| Affiliation: | 1. Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, , Leeds, United Kingdom;2. Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, , Tampa, FL;3. Latvian Biomedical Research and Study Center, , Riga, Latvia;4. Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, , Valencia, Spain;5. Department of Oncology‐Pathology, Karolinska Institutet, Karolinska University Hospital Solna, , Stockholm, Sweden;6. Genetic Epidemiology, German Cancer Research Center, , Heidelberg, Germany;7. Division of Oncology, Department of Clinical Sciences, Lund University, , Lund, Sweden;8. Department of Dermatology, Fundación Instituto Valenciano de Oncología, , Valencia, Spain;9. Division of General Dermatology, Department of Dermatology, Medical University of Vienna, , Vienna, Austria;10. Academic Unit of Oncology, University of Nottingham, , Nottingham, United Kingdom;11. European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group;12. Melanoma Unit, Department of Dermatology, Hospital Clínic de Barcelona, IDIBAPS, Barcelona University, , Barcelona, Spain;13. Centre of Biomedical Research on Rare Diseases (CIBERER), ISCIII, , Barcelona, Spain;14. Department of Dermatology, University Hospital Essen, , Essen, Germany;15. Department of Dermatology, University of Athens School of Medicine, Andreas Sygros Hospital, , Athens, Greece;16. Department of Pathology, University Hospitals, , Leuven, Belgium;17. Melanoma Research Group, Leids Universitair Medisch Centrum, , Leiden, The Netherlands;18. Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals, , Leuven, Belgium |
| 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. |
| Keywords: | melanoma survival PARP1 genetic determinants of survival random effects meta‐analysis bioinformatics |