Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed.
Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach.
Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 × 10-2) and IL4 (rs2070874; HR 1.22; p-value = 1.1 × 10-3) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 × 10-2).
This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.
Prostate cancer and prostatic diseases. 2018 Jan 03 [Epub ahead of print]
L M FitzGerald, S Zhao, A Leonardson, M S Geybels, S Kolb, D W Lin, J L Wright, R Eeles, Z Kote-Jarai, K Govindasami, G G Giles, M C Southey, J Schleutker, T L Tammela, C Sipeky, K L Penney, M J Stampfer, H Gronberg, F Wiklund, P Stattin, J Hugosson, D M Karyadi, E A Ostrander, Z Feng, J L Stanford
Cancer, Genetics and Immunology, Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, 7001, Australia., Biostatistics & Computational Biology Branch, National Institute of Environmental Health Science, Research Triangle Park, NC, 27709, USA., Fred Hutchinson Cancer Research Center, Division of Public Health Science, Seattle, WA, 98109, USA., The Institute of Cancer Research, Sutton, SM2 5NG, UK., Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC, 3004, Australia., Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, VIC, 3010, Australia., Department of Medical Biochemistry and Genetics, Institute of Biomedicine, 20014, University of Turku, Finland., Prostate Cancer Research Center, School of Medicine, University of Tampere, 33100, Tampere, Finland., Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 171 77, Stockholm, Sweden., Department of Surgical Sciences, Uppsala University, 752 36, Uppsala, Sweden., Department of Urology, Institute of Clinical Sciences, University of Göteborgs, 405 30, Göteborgs, Sweden., National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20854, USA., Department of Biostatistics, MD Anderson Cancer Center, Houston, TX, 77030, USA., Fred Hutchinson Cancer Research Center, Division of Public Health Science, Seattle, WA, 98109, USA. .