A Large-Scale Analysis of Genetic Variants within Putative miRNA Binding Sites in Prostate Cancer
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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; Permuth-Wey, Jennifer; Sellers, Thomas A; Srinivasan, Srilakshmi; Eeles, Rosalind; Easton, Doug; Kote-Jarai, Zsofia; Amin Al Olama, Ali; Benlloch, Sara; Muir, Kenneth; Giles, Graham G; Wiklund, Fredrik; Gronberg, Henrik; Haiman, Christopher A; Schleutker, Johanna; Nordestgaard, Børge G; Travis, Ruth C; Neal, David; Pharoah, Paul; Khaw, Kay-Tee; Stanford, Janet L; Blot, William J; Thibodeau, Stephen; Maier, Christiane; Kibel, Adam S; Cybulski, Cezary; Cannon-Albright, Lisa; Brenner, Hermann; Kaneva, Radka; Teixeira, Manuel R; Spurdle, Amanda B; Clements, Judith A; Park, Jong Y; Batra, Jyotsna; PRACTICAL Consortium.
I: Cancer Discovery, Bind 5, Nr. 4, 01.04.2015, s. 368-79.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
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
N1 - ©2015 American Association for Cancer Research.
PY - 2015/4/1
Y1 - 2015/4/1
N2 - 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.
AB - 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.
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
VL - 5
SP - 368
EP - 379
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 4
ER -
ID: 162119121