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 Lin, Jennifer Permuth-Wey, Thomas A Sellers, Srilakshmi Srinivasan, Rosalind A 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 SchleutkerPRACTICAL Consortium, Australian Prostate Cancer BioResource

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29 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 languageEnglish
Pages (from-to)368-379
Number of pages12
JournalCancer Discovery
Volume5
Issue number4
DOIs
Publication statusPublished - 1 Apr 2015

Cite this

Stegeman, S., Amankwah, E., Klein, K., O’Mara, T. A., Kim, D., Lin, H-Y. L., ... Australian Prostate Cancer BioResource (2015). A large-scale analysis of genetic variants within putative miRNA binding sites in prostate cancer. Cancer Discovery, 5(4), 368-379. https://doi.org/10.1158/2159-8290.CD-14-1057
Stegeman, Shane ; Amankwah, Ernest ; Klein, Kerenaftali ; O’Mara, Tracy A. ; Kim, Donghwa ; Lin, Hui-Yi Lin ; Permuth-Wey, Jennifer ; Sellers, Thomas A ; Srinivasan, Srilakshmi ; Eeles, Rosalind A ; Easton, Doug ; Kote-Jarai, Zsofia ; Al Olama, Ali Amin ; Benlloch, Sara ; Muir, Kenneth ; Giles, Graham G. ; Wiklund, Fredrik ; Gronberg, Henrik ; Haiman, Christopher A ; Schleutker, Johanna ; 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.
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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.",
author = "Shane Stegeman and Ernest Amankwah and Kerenaftali Klein and O’Mara, {Tracy A.} and Donghwa Kim and Lin, {Hui-Yi Lin} and Jennifer Permuth-Wey and Sellers, {Thomas A} and Srilakshmi Srinivasan and Eeles, {Rosalind A} 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 {PRACTICAL Consortium} and John Pedersen and Southey, {Melissa C.} and {Australian Prostate Cancer BioResource} and Gail Risbridger and Renea Taylor",
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Stegeman, S, Amankwah, E, Klein, K, O’Mara, TA, Kim, D, Lin, H-YL, Permuth-Wey, J, Sellers, TA, Srinivasan, S, Eeles, RA, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Gronberg, H, Haiman, CA, Schleutker, J, PRACTICAL Consortium & Australian Prostate Cancer BioResource 2015, 'A large-scale analysis of genetic variants within putative miRNA binding sites in prostate cancer', Cancer Discovery, vol. 5, no. 4, pp. 368-379. https://doi.org/10.1158/2159-8290.CD-14-1057

A large-scale analysis of genetic variants within putative miRNA binding sites in prostate cancer. / Stegeman, Shane; Amankwah, Ernest; Klein, Kerenaftali; O’Mara, Tracy A.; Kim, Donghwa; Lin, Hui-Yi Lin; Permuth-Wey, Jennifer; Sellers, Thomas A; Srinivasan, Srilakshmi; Eeles, Rosalind A; Easton, Doug; Kote-Jarai, Zsofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G.; Wiklund, Fredrik; Gronberg, Henrik; Haiman, Christopher A; Schleutker, Johanna; PRACTICAL Consortium; Australian Prostate Cancer BioResource.

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

Research output: Contribution to journalArticleResearchpeer-review

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AU - Stegeman, Shane

AU - Amankwah, Ernest

AU - Klein, Kerenaftali

AU - O’Mara, Tracy A.

AU - Kim, Donghwa

AU - Lin, Hui-Yi Lin

AU - Permuth-Wey, Jennifer

AU - Sellers, Thomas A

AU - Srinivasan, Srilakshmi

AU - Eeles, Rosalind A

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 - PRACTICAL Consortium

AU - Pedersen, John

AU - Southey, Melissa C.

AU - Australian Prostate Cancer BioResource

AU - Risbridger, Gail

AU - Taylor, Renea

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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.

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