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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

Citation

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, 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, 21 pp. 1-10. ISSN 1365-7852 (2018) [Refereed Article]


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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/

DOI: doi:10.1038/s41391-017-0029-2

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 Details

Item Type:Refereed Article
Keywords:prostate cancer, mortality, association study, meta-analysis
Research Division:Medical and Health Sciences
Research Group:Oncology and Carcinogenesis
Research Field:Cancer Genetics
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Cancer and Related Disorders
Author:FitzGerald, LM (Dr Liesel Fitzgerald)
ID Code:123542
Year Published:2018
Deposited By:Menzies Institute for Medical Research
Deposited On:2018-01-11
Last Modified:2018-08-27
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