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A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer.

Al Olama AA, Kote-Jarai Z, Berndt SI, Conti DV, Schumacher F, Han Y, Benlloch S, Hazelett DJ, Wang Z, Saunders E, Leongamornlert D, Lindstrom S, Jugurnauth-Little S, Dadaev T, Tymrakiewicz M, Stram DO, Rand K, Wan P, Stram A, Sheng X, Pooler LC, Park K, Xia L, Tyrer J, Kolonel LN, Le Marchand L, Hoover RN, Machiela MJ, Yeager M, Burdette L, Chung CC, Hutchinson A, Yu K, Goh C, Ahmed M, Govindasami K, Guy M, Tammela TL, Auvinen A, Wahlfors T, Schleutker J, Visakorpi T, Leinonen KA, Xu J, Aly M, Donovan J, Travis RC, Key TJ, Siddiq A, Canzian F, Khaw KT, Takahashi A, Kubo M, Pharoah P, Pashayan N, Weischer M, Nordestgaard BG, Nielsen SF, Klarskov P, Røder MA, Iversen P, Thibodeau SN, McDonnell SK, Schaid DJ, Stanford JL, Kolb S, Holt S, Knudsen B, Coll AH, Gapstur SM, Diver WR, Stevens VL, Maier C, Luedeke M, Herkommer K, Rinckleb AE, Strom SS, Pettaway C, Yeboah ED, Tettey Y, Biritwum RB, Adjei AA, Tay E, Truelove A, Niwa S, Chokkalingam AP, Cannon-Albright L, Cybulski C, Wokołorczyk D, Kluźniak W, Park J, Sellers T, Lin HY, Isaacs WB, Partin AW, Brenner H, Dieffenbach AK, Stegmaier C, Chen C, Giovannucci EL, Ma J, Stampfer M, Penney KL, Mucci L, John EM, Ingles SA, Kittles RA, Murphy AB, Pandha H, Michael A, Kierzek AM, Blot W, Signorello LB, Zheng W, Albanes D, Virtamo J, Weinstein S, Nemesure B, Carpten J, Leske C, Wu SY, Hennis A, Kibel AS, Rybicki BA, Neslund-Dudas C, Hsing AW, Chu L, Goodman PJ, Klein EA, Zheng SL, Batra J, Clements J, Spurdle A, Teixeira MR, Paulo P, Maia S, Slavov C, Kaneva R, Mitev V, Witte JS, Casey G, Gillanders EM, Seminara D, Riboli E, Hamdy FC, Coetzee GA, Li Q, Freedman ML, Hunter DJ, Muir K, Gronberg H, Neal DE, Southey M, Giles GG, Severi G, Breast and Prostate Cancer Cohort Consortium (BPC3)PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) ConsortiumCOGS (Collaborative Oncological Gene-environment Study) ConsortiumGAME-ON/ELLIPSE ConsortiumCook MB, Nakagawa H, Wiklund F, Kraft P, Chanock SJ, Henderson BE, Easton DF, Eeles RA, Haiman CA - Nat. Genet. (2014)

Bottom Line: Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry.Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer.These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

View Article: PubMed Central - PubMed

Affiliation: 1] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [2].

ABSTRACT
Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

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Regional plots of two novel genome-wide significant loci associated with prostate cancer risk. rs1041449/21q22 (TMPRSS2 region, left) and rs17694493/9p21 (CDKN2B-AS1region, right). Top: SNPs are plotted by their position 500kb on either side of the index SNP (purple diamond) on the chromosome against their association (-log10 P) with prostate cancer from the multiethnic meta-analysis (rs1041449) and European meta-analysis (rs17694493). SNPs surrounding the index SNP are colored to indicate the local LD structure using pairwise r2 data from the EUR panel of the 1000 Genomes (March 2012). MIDDLE: Significant peaks from TF and histone modification ChIP-seq experiments in the same genomic window (see Online Methods). All ChIP-seq in LNCaP unless otherwise indicated. BOTTOM: Genomic sequence (enclosed in black box) surrounding the SNP (red box) aligned to a LOGO graphic representing the proposed motif disruption.
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Figure 3: Regional plots of two novel genome-wide significant loci associated with prostate cancer risk. rs1041449/21q22 (TMPRSS2 region, left) and rs17694493/9p21 (CDKN2B-AS1region, right). Top: SNPs are plotted by their position 500kb on either side of the index SNP (purple diamond) on the chromosome against their association (-log10 P) with prostate cancer from the multiethnic meta-analysis (rs1041449) and European meta-analysis (rs17694493). SNPs surrounding the index SNP are colored to indicate the local LD structure using pairwise r2 data from the EUR panel of the 1000 Genomes (March 2012). MIDDLE: Significant peaks from TF and histone modification ChIP-seq experiments in the same genomic window (see Online Methods). All ChIP-seq in LNCaP unless otherwise indicated. BOTTOM: Genomic sequence (enclosed in black box) surrounding the SNP (red box) aligned to a LOGO graphic representing the proposed motif disruption.

Mentions: A number of the novel susceptibility regions are located in close proximity to genes which have either an established role, or have been directly implicated, in cancer (Table 1). The most notable is rs1041449 on chromosome 21q22, which is situated 20kb 5′ of theTMPRSS2 gene which encodes a member of a serine protease family.16 Expression of TMPRSS2 is highly specific to prostate tissue and chromosomal translocation resulting in fusion of the TMPRSS2 promoter/enhancer region with the ETS transcription factors ERG and ETV1 are frequently observed in prostate cancer.17 In analyzing data of 552 tumors characterized for the TMPRSS2-ERG fusion (46% positive) (Online Methods), we found no evidence of an association between the risk allele and fusion status (p=0.53; Supplementary Table 15). The variant risk rs1041449 is located within a number of histone marks and TF occupancy sites in the predicted enhancer region of TMPRSS2 (Figure 3) however we found little evidence that this variant influences TMPRSS2 expression in prostate tumors (n=244, P=0.60), or in normal prostate tissue (n=87, P=0.62) (Online Methods).


A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer.

Al Olama AA, Kote-Jarai Z, Berndt SI, Conti DV, Schumacher F, Han Y, Benlloch S, Hazelett DJ, Wang Z, Saunders E, Leongamornlert D, Lindstrom S, Jugurnauth-Little S, Dadaev T, Tymrakiewicz M, Stram DO, Rand K, Wan P, Stram A, Sheng X, Pooler LC, Park K, Xia L, Tyrer J, Kolonel LN, Le Marchand L, Hoover RN, Machiela MJ, Yeager M, Burdette L, Chung CC, Hutchinson A, Yu K, Goh C, Ahmed M, Govindasami K, Guy M, Tammela TL, Auvinen A, Wahlfors T, Schleutker J, Visakorpi T, Leinonen KA, Xu J, Aly M, Donovan J, Travis RC, Key TJ, Siddiq A, Canzian F, Khaw KT, Takahashi A, Kubo M, Pharoah P, Pashayan N, Weischer M, Nordestgaard BG, Nielsen SF, Klarskov P, Røder MA, Iversen P, Thibodeau SN, McDonnell SK, Schaid DJ, Stanford JL, Kolb S, Holt S, Knudsen B, Coll AH, Gapstur SM, Diver WR, Stevens VL, Maier C, Luedeke M, Herkommer K, Rinckleb AE, Strom SS, Pettaway C, Yeboah ED, Tettey Y, Biritwum RB, Adjei AA, Tay E, Truelove A, Niwa S, Chokkalingam AP, Cannon-Albright L, Cybulski C, Wokołorczyk D, Kluźniak W, Park J, Sellers T, Lin HY, Isaacs WB, Partin AW, Brenner H, Dieffenbach AK, Stegmaier C, Chen C, Giovannucci EL, Ma J, Stampfer M, Penney KL, Mucci L, John EM, Ingles SA, Kittles RA, Murphy AB, Pandha H, Michael A, Kierzek AM, Blot W, Signorello LB, Zheng W, Albanes D, Virtamo J, Weinstein S, Nemesure B, Carpten J, Leske C, Wu SY, Hennis A, Kibel AS, Rybicki BA, Neslund-Dudas C, Hsing AW, Chu L, Goodman PJ, Klein EA, Zheng SL, Batra J, Clements J, Spurdle A, Teixeira MR, Paulo P, Maia S, Slavov C, Kaneva R, Mitev V, Witte JS, Casey G, Gillanders EM, Seminara D, Riboli E, Hamdy FC, Coetzee GA, Li Q, Freedman ML, Hunter DJ, Muir K, Gronberg H, Neal DE, Southey M, Giles GG, Severi G, Breast and Prostate Cancer Cohort Consortium (BPC3)PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) ConsortiumCOGS (Collaborative Oncological Gene-environment Study) ConsortiumGAME-ON/ELLIPSE ConsortiumCook MB, Nakagawa H, Wiklund F, Kraft P, Chanock SJ, Henderson BE, Easton DF, Eeles RA, Haiman CA - Nat. Genet. (2014)

Regional plots of two novel genome-wide significant loci associated with prostate cancer risk. rs1041449/21q22 (TMPRSS2 region, left) and rs17694493/9p21 (CDKN2B-AS1region, right). Top: SNPs are plotted by their position 500kb on either side of the index SNP (purple diamond) on the chromosome against their association (-log10 P) with prostate cancer from the multiethnic meta-analysis (rs1041449) and European meta-analysis (rs17694493). SNPs surrounding the index SNP are colored to indicate the local LD structure using pairwise r2 data from the EUR panel of the 1000 Genomes (March 2012). MIDDLE: Significant peaks from TF and histone modification ChIP-seq experiments in the same genomic window (see Online Methods). All ChIP-seq in LNCaP unless otherwise indicated. BOTTOM: Genomic sequence (enclosed in black box) surrounding the SNP (red box) aligned to a LOGO graphic representing the proposed motif disruption.
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Related In: Results  -  Collection

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Figure 3: Regional plots of two novel genome-wide significant loci associated with prostate cancer risk. rs1041449/21q22 (TMPRSS2 region, left) and rs17694493/9p21 (CDKN2B-AS1region, right). Top: SNPs are plotted by their position 500kb on either side of the index SNP (purple diamond) on the chromosome against their association (-log10 P) with prostate cancer from the multiethnic meta-analysis (rs1041449) and European meta-analysis (rs17694493). SNPs surrounding the index SNP are colored to indicate the local LD structure using pairwise r2 data from the EUR panel of the 1000 Genomes (March 2012). MIDDLE: Significant peaks from TF and histone modification ChIP-seq experiments in the same genomic window (see Online Methods). All ChIP-seq in LNCaP unless otherwise indicated. BOTTOM: Genomic sequence (enclosed in black box) surrounding the SNP (red box) aligned to a LOGO graphic representing the proposed motif disruption.
Mentions: A number of the novel susceptibility regions are located in close proximity to genes which have either an established role, or have been directly implicated, in cancer (Table 1). The most notable is rs1041449 on chromosome 21q22, which is situated 20kb 5′ of theTMPRSS2 gene which encodes a member of a serine protease family.16 Expression of TMPRSS2 is highly specific to prostate tissue and chromosomal translocation resulting in fusion of the TMPRSS2 promoter/enhancer region with the ETS transcription factors ERG and ETV1 are frequently observed in prostate cancer.17 In analyzing data of 552 tumors characterized for the TMPRSS2-ERG fusion (46% positive) (Online Methods), we found no evidence of an association between the risk allele and fusion status (p=0.53; Supplementary Table 15). The variant risk rs1041449 is located within a number of histone marks and TF occupancy sites in the predicted enhancer region of TMPRSS2 (Figure 3) however we found little evidence that this variant influences TMPRSS2 expression in prostate tumors (n=244, P=0.60), or in normal prostate tissue (n=87, P=0.62) (Online Methods).

Bottom Line: Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry.Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer.These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

View Article: PubMed Central - PubMed

Affiliation: 1] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [2].

ABSTRACT
Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

Show MeSH
Related in: MedlinePlus