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Prostate Cancer Prostatic Dis. 2018 Jun;21(2):228-237. doi: 10.1038/s41391-017-0029-2. Epub 2018 Jan 3.

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

Author information

1
Cancer, Genetics and Immunology, Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, 7001, Australia.
2
Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC, 3004, Australia.
3
Biostatistics & Computational Biology Branch, National Institute of Environmental Health Science, Research Triangle Park, NC, 27709, USA.
4
Fred Hutchinson Cancer Research Center, Division of Public Health Science, Seattle, WA, 98109, USA.
5
Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, 6211 LK, Maastricht, The Netherlands.
6
Department of Urology, University of Washington, School of Medicine, Seattle, WA, 98195, USA.
7
The Institute of Cancer Research, Sutton, SM2 5NG, UK.
8
Royal Marsden National Health Service Foundation Trust, London and Sutton, SW3 6JJ, UK.
9
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Carlton, VIC, 3053, Australia.
10
Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, VIC, 3010, Australia.
11
Department of Medical Biochemistry and Genetics, Institute of Biomedicine, 20014, University of Turku, Finland.
12
Tuch Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, 20520, Turku, Finland.
13
Prostate Cancer Research Center, School of Medicine, University of Tampere, 33100, Tampere, Finland.
14
Department of Urology, Tampere University Hospital, 33521, Tampere, Finland.
15
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
16
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
17
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
18
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 171 77, Stockholm, Sweden.
19
Department of Surgical Sciences, Uppsala University, 752 36, Uppsala, Sweden.
20
Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, 901 87, Umeå, Sweden.
21
Department of Urology, Institute of Clinical Sciences, University of Göteborgs, 405 30, Göteborgs, Sweden.
22
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20854, USA.
23
Department of Biostatistics, MD Anderson Cancer Center, Houston, TX, 77030, USA.
24
Fred Hutchinson Cancer Research Center, Division of Public Health Science, Seattle, WA, 98109, USA. jstanfor@fredhutch.org.
25
Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, 98195, USA. jstanfor@fredhutch.org.

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.

PMID:
29298992
PMCID:
PMC6026113
DOI:
10.1038/s41391-017-0029-2
[Indexed for MEDLINE]
Free PMC Article

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