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

Shane Stegeman; Ernest Amankwah; Kerenaftali Klein; Tracy A O'Mara; Donghwa Kim; Hui-Yi Lin; Jennifer Permuth-Wey; Thomas A Sellers; Srilakshmi Srinivasan; Rosalind Eeles; Doug Easton; Zsofia Kote-Jarai; Ali Amin Al Olama; Sara Benlloch; Kenneth Muir; Graham G Giles; Fredrik Wiklund; Henrik Gronberg; Christopher A Haiman; Johanna Schleutker; Børge G Nordestgaard; Ruth C Travis; David Neal; Paul Pharoah; Kay-Tee Khaw; Janet L Stanford; William J Blot; Stephen Thibodeau; Christiane Maier; Adam S Kibel; Cezary Cybulski; Lisa Cannon-Albright; Hermann Brenner; Radka Kaneva; Manuel R Teixeira; Amanda B Spurdle; Judith A Clements; Jong Y Park; Jyotsna Batra; PRACTICAL Consortium

doi:10.1158/2159-8290.cd-14-1057

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

Shane Stegeman, Ernest Amankwah, Kerenaftali Klein, Tracy A O'Mara, Donghwa Kim, Hui-Yi Lin, Jennifer Permuth-Wey, Thomas A Sellers, Srilakshmi Srinivasan, Rosalind Eeles, Doug Easton, Zsofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Kenneth Muir, Graham G Giles, Fredrik Wiklund, Henrik Gronberg, Christopher A Haiman, Johanna SchleutkerBørge G Nordestgaard, Ruth C Travis, David Neal, Paul Pharoah, Kay-Tee Khaw, Janet L Stanford, William J Blot, Stephen Thibodeau, Christiane Maier, Adam S Kibel, Cezary Cybulski, Lisa Cannon-Albright, Hermann Brenner, Radka Kaneva, Manuel R Teixeira, Amanda B Spurdle, Judith A Clements, Jong Y Park, Jyotsna Batra, PRACTICAL Consortium

Department of Clinical Medicine

39 Citations (Scopus)

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 language	English
Journal	Cancer Discovery
Volume	5
Issue number	4
Pages (from-to)	368-79
Number of pages	12
ISSN	2159-8274
DOIs	https://doi.org/10.1158/2159-8290.cd-14-1057
Publication status	Published - 1 Apr 2015

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Stegeman, S., Amankwah, E., Klein, K., O'Mara, T. A., Kim, D., Lin, H-Y., Permuth-Wey, J., Sellers, T. A., Srinivasan, S., Eeles, R., Easton, D., Kote-Jarai, Z., Amin Al Olama, A., Benlloch, S., Muir, K., Giles, G. G., Wiklund, F., Gronberg, H., Haiman, C. A., ... PRACTICAL Consortium (2015). A Large-Scale Analysis of Genetic Variants within Putative miRNA Binding Sites in Prostate Cancer. Cancer Discovery, 5(4), 368-79. https://doi.org/10.1158/2159-8290.cd-14-1057

Stegeman, S, Amankwah, E, Klein, K, O'Mara, TA, Kim, D, Lin, H-Y, 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, K-T, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Kaneva, R, Teixeira, MR, Spurdle, AB, Clements, JA, Park, JY, Batra, J & PRACTICAL Consortium 2015, 'A Large-Scale Analysis of Genetic Variants within Putative miRNA Binding Sites in Prostate Cancer', Cancer Discovery, vol. 5, no. 4, pp. 368-79. https://doi.org/10.1158/2159-8290.cd-14-1057

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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.",

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T1 - A Large-Scale Analysis of Genetic Variants within Putative miRNA Binding Sites in Prostate Cancer

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 - Amin Al Olama, Ali

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 - PRACTICAL Consortium

PY - 2015/4/1

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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.

KW - 3' Untranslated Regions

KW - Adult

KW - Aged

KW - Alleles

KW - Binding Sites

KW - Case-Control Studies

KW - Cluster Analysis

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Genetic Variation

KW - Genotype

KW - Humans

KW - Kallikreins

KW - Male

KW - MicroRNAs

KW - Middle Aged

KW - Neoplasm Grading

KW - Neoplasm Staging

KW - Polymorphism, Single Nucleotide

KW - Prostate-Specific Antigen

KW - Prostatic Neoplasms

KW - Quantitative Trait Loci

KW - R-SNARE Proteins

KW - RNA, Messenger

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

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

M3 - Journal article

C2 - 25691096

SN - 2159-8274

VL - 5

SP - 368

EP - 379

JO - Cancer Discovery

JF - Cancer Discovery

IS - 4

ER -

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

Abstract

Keywords

UN SDGs

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