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

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. StattinJ. Hugosson, D. M. Karyadi, E. A. Ostrander, Z. Feng, J. L. Stanford*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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 x 10(-2)) and IL4 (rs2070874; HR 1.22; p-value = 1.1 x 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 x 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.
Original languageEnglish
Pages (from-to)228-237
Number of pages10
JournalProstate Cancer and Prostatic Diseases
Volume21
Issue number2
DOIs
Publication statusPublished - 1 Jun 2018

Keywords

  • DNA-REPAIR GENES
  • O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE
  • RACIAL DISPARITIES
  • CARCINOMA-CELLS
  • RISK
  • INTERLEUKIN-4
  • PATHWAY
  • GROWTH
  • FAMILIES
  • EXPRESSION

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