Faculty Collaboration Database

A Large-Scale Analysis of Genetic Variants within Putative miRNA Binding Sites in Prostate Cancer. Cancer Discov 2015 Apr;5(4):368-79

Date

02/19/2015

Pubmed ID

25691096

Pubmed Central ID

PMC4390388

DOI

10.1158/2159-8290.CD-14-1057

Scopus ID

2-s2.0-85000352081 (requires institutional sign-in at Scopus site)   51 Citations

Abstract

UNLABELLED: 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.

Author List

Stegeman S, Amankwah E, Klein K, O'Mara TA, Kim D, Lin HY, Permuth-Wey J, Sellers TA, Srinivasan S, Eeles R, Easton D, Kote-Jarai Z, Amin Al Olama A, Benlloch S, Muir K, Giles GG, Wiklund F, Gronberg H, Haiman CA, Schleutker J, Nordestgaard BG, Travis RC, Neal D, Pharoah P, Khaw KT, Stanford JL, Blot WJ, Thibodeau S, Maier C, Kibel AS, Cybulski C, Cannon-Albright L, Brenner H, Kaneva R, Teixeira MR, PRACTICAL Consortium, Australian Prostate Cancer BioResource, Spurdle AB, Clements JA, Park JY, Batra J

Author

Ernest Amankwah PhD Director, Associate Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

3' Untranslated Regions
Adult
Aged
Alleles
Binding Sites
Case-Control Studies
Cluster Analysis
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genetic Variation
Genotype
Humans
Kallikreins
Male
MicroRNAs
Middle Aged
Neoplasm Grading
Neoplasm Staging
Polymorphism, Single Nucleotide
Prostate-Specific Antigen
Prostatic Neoplasms
Quantitative Trait Loci
R-SNARE Proteins
RNA, Messenger