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Cancer Discov. 2015 Apr;5(4):368-79. doi: 10.1158/2159-8290.CD-14-1057. Epub 2015 Feb 17.

A Large-Scale Analysis of Genetic Variants within Putative miRNA Binding Sites in Prostate Cancer.

Author information

1
Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Translational Research Institute, Queensland University of Technology, Brisbane, Australia.
2
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida.
3
Statistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
4
Molecular Cancer Epidemiology Laboratory, Genetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
5
Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida.
6
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida.
7
The Institute of Cancer Research, London, United Kingdom. Royal Marsden NHS Foundation Trust, Fulham and Sutton, London and Surrey, United Kingdom.
8
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Cambridge, United Kingdom.
9
The Institute of Cancer Research, London, United Kingdom.
10
University of Warwick, Coventry, United Kingdom.
11
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
12
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
13
Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California.
14
Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland. Institute of Biomedical Technology/BioMediTech, University of Tampere and FimLab Laboratories, Tampere, Finland.
15
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
16
Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
17
Surgical Oncology (Uro-Oncology: S4), University of Cambridge, Addenbrooke's Hospital, Cambridge; Cancer Research UK, Cambridge Research Institute, Cambridge, United Kingdom.
18
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Laboratory, Cambridge, United Kingdom.
19
Cambridge Institute of Public Health, University of Cambridge, Cambridge, United Kingdom.
20
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington.
21
International Epidemiology Institute, Rockville, Maryland.
22
Mayo Clinic, Rochester, Minnesota.
23
Department of Urology, University Hospital Ulm, Ulm, Germany. Institute of Human Genetics, University Hospital Ulm, Ulm, Germany.
24
Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts. Washington University, St. Louis, Missouri.
25
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
26
Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah.
27
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany.
28
Molecular Medicine Center and Department of Medical Chemistry and Biochemistry, Medical University-Sofia, Sofia, Bulgaria.
29
Department of Genetics, Portuguese Oncology Institute, Porto; Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal.
30
Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Translational Research Institute, Queensland University of Technology, Brisbane, Australia. jyotsna.batra@qut.edu.au.

Abstract

Prostate cancer is the second most common malignancy among men worldwide. Genome-wide association studies have identified 100 risk variants for prostate cancer, which can explain approximately 33% of the familial risk of the disease. We hypothesized that a comprehensive analysis of genetic variations found within the 3' untranslated region of genes predicted to affect miRNA binding (miRSNP) can identify additional prostate cancer risk variants. We investigated the association between 2,169 miRSNPs and prostate cancer risk in a large-scale analysis of 22,301 cases and 22,320 controls of European ancestry from 23 participating studies. Twenty-two miRSNPs were associated (P<2.3×10(-5)) with risk of prostate cancer, 10 of which were within 7 genes previously not mapped by GWAS studies. Further, using miRNA mimics and reporter gene assays, we showed that miR-3162-5p has specific affinity for the KLK3 rs1058205 miRSNP T-allele, whereas miR-370 has greater affinity for the VAMP8 rs1010 miRSNP A-allele, validating their functional role.

SIGNIFICANCE:

Findings from this large association study suggest that a focus on miRSNPs, including functional evaluation, can identify candidate risk loci below currently accepted statistical levels of genome-wide significance. Studies of miRNAs and their interactions with SNPs could provide further insights into the mechanisms of prostate cancer risk.

PMID:
25691096
PMCID:
PMC4390388
DOI:
10.1158/2159-8290.CD-14-1057
[Indexed for MEDLINE]
Free PMC Article

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