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Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality: An analysis of 12,082 prostate cancer cases

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FitzGerald, LM ORCID: 0000-0002-6882-2698, Zhao, S, Leonardson, A, Geybels, MS, Kolb, S, Lin, DW, Wright, JL, Eeles, R, Kote-Jarai, Z, Govindasami, K, Giles, GG, Southey, MC, Schleutker, J, Tammela, TL, Sipeky, C, Penney, KL, Stampfer, MJ, Gronberg, H, Wiklund, F, Stattin, P, Hugosson, J, Karyadi, DM, Ostrander, EA, Feng, Z and Stanford, JL 2018 , 'Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality: An analysis of 12,082 prostate cancer cases' , Prostate Cancer and Prostatic Diseases, vol. 21 , pp. 1-10 , doi: 10.1038/s41391-017-0029-2.

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Abstract

Background: 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.Methods: 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.Results: 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).Conclusions: 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.

Item Type: Article
Authors/Creators:FitzGerald, LM and Zhao, S and Leonardson, A and Geybels, MS and Kolb, S and Lin, DW and Wright, JL and Eeles, R and Kote-Jarai, Z and Govindasami, K and Giles, GG and Southey, MC and Schleutker, J and Tammela, TL and Sipeky, C and Penney, KL and Stampfer, MJ and Gronberg, H and Wiklund, F and Stattin, P and Hugosson, J and Karyadi, DM and Ostrander, EA and Feng, Z and Stanford, JL
Keywords: prostate cancer, mortality, association study, meta-analysis
Journal or Publication Title: Prostate Cancer and Prostatic Diseases
Publisher: Nature Publishing Group
ISSN: 1365-7852
DOI / ID Number: 10.1038/s41391-017-0029-2
Copyright Information:

Copyright 2017 The Authors. Licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) https://creativecommons.org/licenses/by-nc-sa/4.0/

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