A large-scale analysis of genetic variants within putative miRNA binding sites in prostate cancer

PRACTICAL Consortium, Australian Prostate Cancer BioResource

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)368-379
Number of pages12
JournalCancer Discovery
Volume5
Issue number4
DOIs
StatePublished - Apr 1 2015
Externally publishedYes

Fingerprint

MicroRNAs
Prostatic Neoplasms
Binding Sites
Genome-Wide Association Study
Alleles
3' Untranslated Regions
Reporter Genes
Genes
Single Nucleotide Polymorphism
Genome
Neoplasms

ASJC Scopus subject areas

  • Oncology

Cite this

A large-scale analysis of genetic variants within putative miRNA binding sites in prostate cancer. / PRACTICAL Consortium; Australian Prostate Cancer BioResource.

In: Cancer Discovery, Vol. 5, No. 4, 01.04.2015, p. 368-379.

Research output: Contribution to journalArticle

PRACTICAL Consortium ; Australian Prostate Cancer BioResource. / A large-scale analysis of genetic variants within putative miRNA binding sites in prostate cancer. In: Cancer Discovery. 2015 ; Vol. 5, No. 4. pp. 368-379.
@article{d6fd399fd1b048cdb3e3576aebb19d46,
title = "A large-scale analysis of genetic variants within putative miRNA binding sites in prostate cancer",
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.",
author = "{PRACTICAL Consortium} and {Australian Prostate Cancer BioResource} and Shane Stegeman and Ernest Amankwah and Kerenaftali Klein and O’Mara, {Tracy A.} and Donghwa Kim and Lin, {Hui Yi} and Jennifer Permuth-Wey and Sellers, {Thomas A.} and Srilakshmi Srinivasan and Rosalind Eeles and Doug Easton and Zsofia Kote-Jarai and {Al Olama}, {Ali Amin} and Sara Benlloch and Kenneth Muir and Giles, {Graham G.} and Fredrik Wiklund and Henrik Gronberg and Haiman, {Christopher A.} and Johanna Schleutker and Nordestgaard, {B{\o}rge G.} and Travis, {Ruth C.} and David Neal and Paul Pharoah and Khaw, {Kay Tee} and Stanford, {Janet L.} and Blot, {William J.} and Stephen Thibodeau and Christiane Maier and Kibel, {Adam S.} and Cezary Cybulski and Lisa Cannon-Albright and Hermann Brenner and Radka Kaneva and Teixeira, {Manuel R.} and Spurdle, {Amanda B.} and Clements, {Judith A.} and Park, {Jong Y.} and Jyotsna Batra and Margaret Cook and Angela Morgan and Artitaya Lophatananon and Cyril Fisher and Daniel Leongamornlert and Saunders, {Edward J.} and Sawyer, {Emma J.} and Koveela Govindasami and Malgorzata Tymrakiewicz and Michelle Guy and Naomi Livni",
year = "2015",
month = "4",
day = "1",
doi = "10.1158/2159-8290.CD-14-1057",
language = "English (US)",
volume = "5",
pages = "368--379",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "4",

}

TY - JOUR

T1 - A large-scale analysis of genetic variants within putative miRNA binding sites in prostate cancer

AU - PRACTICAL Consortium

AU - Australian Prostate Cancer BioResource

AU - Stegeman, Shane

AU - Amankwah, Ernest

AU - Klein, Kerenaftali

AU - O’Mara, Tracy A.

AU - Kim, Donghwa

AU - Lin, Hui Yi

AU - Permuth-Wey, Jennifer

AU - Sellers, Thomas A.

AU - Srinivasan, Srilakshmi

AU - Eeles, Rosalind

AU - Easton, Doug

AU - Kote-Jarai, Zsofia

AU - Al Olama, Ali Amin

AU - Benlloch, Sara

AU - Muir, Kenneth

AU - Giles, Graham G.

AU - Wiklund, Fredrik

AU - Gronberg, Henrik

AU - Haiman, Christopher A.

AU - Schleutker, Johanna

AU - Nordestgaard, Børge G.

AU - Travis, Ruth C.

AU - Neal, David

AU - Pharoah, Paul

AU - Khaw, Kay Tee

AU - Stanford, Janet L.

AU - Blot, William J.

AU - Thibodeau, Stephen

AU - Maier, Christiane

AU - Kibel, Adam S.

AU - Cybulski, Cezary

AU - Cannon-Albright, Lisa

AU - Brenner, Hermann

AU - Kaneva, Radka

AU - Teixeira, Manuel R.

AU - Spurdle, Amanda B.

AU - Clements, Judith A.

AU - Park, Jong Y.

AU - Batra, Jyotsna

AU - Cook, Margaret

AU - Morgan, Angela

AU - Lophatananon, Artitaya

AU - Fisher, Cyril

AU - Leongamornlert, Daniel

AU - Saunders, Edward J.

AU - Sawyer, Emma J.

AU - Govindasami, Koveela

AU - Tymrakiewicz, Malgorzata

AU - Guy, Michelle

AU - Livni, Naomi

PY - 2015/4/1

Y1 - 2015/4/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85000352081&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85000352081&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-14-1057

DO - 10.1158/2159-8290.CD-14-1057

M3 - Article

C2 - 25691096

AN - SCOPUS:85000352081

VL - 5

SP - 368

EP - 379

JO - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

IS - 4

ER -