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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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Manhattan Plot of results from the multiethnic meta-analysis of overall prostate cancer risk. All SNPs within 500kb of known GWAS SNPs are omitted. The green line represents P=5×10-8. This figure shows all new variants with P<5×10-8, regardless of the confirmation results, as well as signals that were reported in the European meta-analysis that also reached 5×10-8 in the multiethnic meta-analysis (see Table 1 and Supplementary Table 6).
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Figure 2: Manhattan Plot of results from the multiethnic meta-analysis of overall prostate cancer risk. All SNPs within 500kb of known GWAS SNPs are omitted. The green line represents P=5×10-8. This figure shows all new variants with P<5×10-8, regardless of the confirmation results, as well as signals that were reported in the European meta-analysis that also reached 5×10-8 in the multiethnic meta-analysis (see Table 1 and Supplementary Table 6).

Mentions: No novel risk loci were revealed in ethnic-specific analyses within the African, Japanese or Latino ancestry populations possibly due to lack of power (Supplemental Figure 2). However, in combining results across populations in a multiethnic meta-analysis (43,303 cases, 43,737 controls), 11additional variants were identified in association with prostate cancer risk in novel risk regions at P<5×10-8 (Table 1; Supplemental Table 5; Figure 2). We confirmed the imputed genotypes for 7 variants which had high imputation information scores (r2 range, 0.81-1) through additional genotyping and sequencing (Online Methods,Supplementary Tables 6-8). All 7 variants were nominally associated with risk (P<0.05) in at least one of the non-European ancestry populations and the per-allele effects were directionally consistent across all 4 populations for 6 of the 7 variants. All variants had MAFs≥0.05 in all four populations, and no significant evidence of population heterogeneity was noted with any of these 7 variants (Table 1).


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)

Manhattan Plot of results from the multiethnic meta-analysis of overall prostate cancer risk. All SNPs within 500kb of known GWAS SNPs are omitted. The green line represents P=5×10-8. This figure shows all new variants with P<5×10-8, regardless of the confirmation results, as well as signals that were reported in the European meta-analysis that also reached 5×10-8 in the multiethnic meta-analysis (see Table 1 and Supplementary Table 6).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383163&req=5

Figure 2: Manhattan Plot of results from the multiethnic meta-analysis of overall prostate cancer risk. All SNPs within 500kb of known GWAS SNPs are omitted. The green line represents P=5×10-8. This figure shows all new variants with P<5×10-8, regardless of the confirmation results, as well as signals that were reported in the European meta-analysis that also reached 5×10-8 in the multiethnic meta-analysis (see Table 1 and Supplementary Table 6).
Mentions: No novel risk loci were revealed in ethnic-specific analyses within the African, Japanese or Latino ancestry populations possibly due to lack of power (Supplemental Figure 2). However, in combining results across populations in a multiethnic meta-analysis (43,303 cases, 43,737 controls), 11additional variants were identified in association with prostate cancer risk in novel risk regions at P<5×10-8 (Table 1; Supplemental Table 5; Figure 2). We confirmed the imputed genotypes for 7 variants which had high imputation information scores (r2 range, 0.81-1) through additional genotyping and sequencing (Online Methods,Supplementary Tables 6-8). All 7 variants were nominally associated with risk (P<0.05) in at least one of the non-European ancestry populations and the per-allele effects were directionally consistent across all 4 populations for 6 of the 7 variants. All variants had MAFs≥0.05 in all four populations, and no significant evidence of population heterogeneity was noted with any of these 7 variants (Table 1).

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