Association between two unlinked loci at 8q24 and prostate cancer risk among European Americans

S. Lilly Zheng, Jielin Sun, Yu Cheng, Ge Li, Fang Chi Hsu, Yi Zhu, Bao Li Chang, Wennuan Liu, Jin Woo Kim, Aubrey R. Turner, Marta Gielzak, Guifang Yan, Sarah D. Isaacs, Kathleen E. Wiley, Jurga Sauvageot, Huann Sheng Chen, Robin Gurganus, Leslie A. Mangold, Bruce Trock, Henrik GronbergDavid Duggan, John D. Carpten, Alan Wayne Partin, Patrick Walsh, Jianfeng Xu, William B Isaacs

Research output: Contribution to journalArticle

Abstract

Background: Recent studies have provided evidence of associations between genetic markers at human chromosome 8q24 and an increased risk of prostate cancer. We examined whether multiple independent risk variants exist in this region and whether the strength of observed associations differs as a function of disease aggressiveness. Methods: We evaluated associations between 18 single-nucleotide polymorphisms (SNPs) in a 1-Mb interval at 8q24 and the risk of prostate cancer among 1563 case patients (1017 of whom had high-grade [Gleason score ≥7] and/or non-organ-confined disease) and 576 control subjects of European American ancestry. Differences in genotype frequencies between case and control subjects were compared using logistic regression analysis, with adjustment for age, and the Wald chi-square test. All statistical tests were two-sided. Results: We identified multiple SNPs in a 50-kb region (referred to as locus 1) that are in linkage disequilibrium with a previously reported risk-associated SNP at 8q24, rs1447295, but were more strongly associated with prostate cancer risk in our study population. We also identified a novel susceptibility SNP, rs6983267, at a second locus (locus 2) that is approximately 70 kb centromeric of rs1447295 and in linkage equilibrium with, and independent of, locus 1. Risk alleles at locus 2 were common in our study population (minor allele frequency ∼50%, 25% homozygous for risk-associated allele). Analysis of the National Cancer Institute's Cancer Genetic Markers of Susceptibility (CGEMS) prostate cancer association study database alone and in combination with our data provided further evidence for this second prostate cancer risk locus; in the combined analysis, the allele frequencies for rs6983267 differed statistically significantly between case patients and control subjects (P = 1.61 × 10-9). We also identified a third locus at 8q24, approximately 400 kb centromeric to locus 2, that was statistically significantly associated with prostate cancer risk in a combined analysis of our data and CGEMS study data (P = 6.8 × 10-4). A joint analysis of loci 1 and 2 indicated that 35% of the control subjects carried risk genotypes at one or both these loci; compared with men with the nonrisk genotype at both loci, men with risk genotypes at both loci had an odds ratio of prostate cancer of 2.68 (95% confidence interval [CI] = 1.62 to 4.43) and men with risk genotypes at either locus had an odds ratio of prostate cancer of 1.70 (95% CI = 1.39 to 2.07). Conclusions: Three loci at 8q24 are independent genetic risk factors for prostate cancer.

Original languageEnglish (US)
Pages (from-to)1525-1533
Number of pages9
JournalJournal of the National Cancer Institute
Volume99
Issue number20
DOIs
StatePublished - Oct 2007

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Prostatic Neoplasms
Genotype
Single Nucleotide Polymorphism
Genetic Markers
Genetic Predisposition to Disease
Gene Frequency
Alleles
Odds Ratio
Confidence Intervals
Second Primary Neoplasms
National Cancer Institute (U.S.)
Neoplasm Grading
Linkage Disequilibrium
Human Chromosomes
Chi-Square Distribution
Population
Neoplasms
Logistic Models
Regression Analysis
Databases

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Association between two unlinked loci at 8q24 and prostate cancer risk among European Americans. / Zheng, S. Lilly; Sun, Jielin; Cheng, Yu; Li, Ge; Hsu, Fang Chi; Zhu, Yi; Chang, Bao Li; Liu, Wennuan; Kim, Jin Woo; Turner, Aubrey R.; Gielzak, Marta; Yan, Guifang; Isaacs, Sarah D.; Wiley, Kathleen E.; Sauvageot, Jurga; Chen, Huann Sheng; Gurganus, Robin; Mangold, Leslie A.; Trock, Bruce; Gronberg, Henrik; Duggan, David; Carpten, John D.; Partin, Alan Wayne; Walsh, Patrick; Xu, Jianfeng; Isaacs, William B.

In: Journal of the National Cancer Institute, Vol. 99, No. 20, 10.2007, p. 1525-1533.

Research output: Contribution to journalArticle

Zheng, SL, Sun, J, Cheng, Y, Li, G, Hsu, FC, Zhu, Y, Chang, BL, Liu, W, Kim, JW, Turner, AR, Gielzak, M, Yan, G, Isaacs, SD, Wiley, KE, Sauvageot, J, Chen, HS, Gurganus, R, Mangold, LA, Trock, B, Gronberg, H, Duggan, D, Carpten, JD, Partin, AW, Walsh, P, Xu, J & Isaacs, WB 2007, 'Association between two unlinked loci at 8q24 and prostate cancer risk among European Americans', Journal of the National Cancer Institute, vol. 99, no. 20, pp. 1525-1533. https://doi.org/10.1093/jnci/djm169
Zheng, S. Lilly ; Sun, Jielin ; Cheng, Yu ; Li, Ge ; Hsu, Fang Chi ; Zhu, Yi ; Chang, Bao Li ; Liu, Wennuan ; Kim, Jin Woo ; Turner, Aubrey R. ; Gielzak, Marta ; Yan, Guifang ; Isaacs, Sarah D. ; Wiley, Kathleen E. ; Sauvageot, Jurga ; Chen, Huann Sheng ; Gurganus, Robin ; Mangold, Leslie A. ; Trock, Bruce ; Gronberg, Henrik ; Duggan, David ; Carpten, John D. ; Partin, Alan Wayne ; Walsh, Patrick ; Xu, Jianfeng ; Isaacs, William B. / Association between two unlinked loci at 8q24 and prostate cancer risk among European Americans. In: Journal of the National Cancer Institute. 2007 ; Vol. 99, No. 20. pp. 1525-1533.
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title = "Association between two unlinked loci at 8q24 and prostate cancer risk among European Americans",
abstract = "Background: Recent studies have provided evidence of associations between genetic markers at human chromosome 8q24 and an increased risk of prostate cancer. We examined whether multiple independent risk variants exist in this region and whether the strength of observed associations differs as a function of disease aggressiveness. Methods: We evaluated associations between 18 single-nucleotide polymorphisms (SNPs) in a 1-Mb interval at 8q24 and the risk of prostate cancer among 1563 case patients (1017 of whom had high-grade [Gleason score ≥7] and/or non-organ-confined disease) and 576 control subjects of European American ancestry. Differences in genotype frequencies between case and control subjects were compared using logistic regression analysis, with adjustment for age, and the Wald chi-square test. All statistical tests were two-sided. Results: We identified multiple SNPs in a 50-kb region (referred to as locus 1) that are in linkage disequilibrium with a previously reported risk-associated SNP at 8q24, rs1447295, but were more strongly associated with prostate cancer risk in our study population. We also identified a novel susceptibility SNP, rs6983267, at a second locus (locus 2) that is approximately 70 kb centromeric of rs1447295 and in linkage equilibrium with, and independent of, locus 1. Risk alleles at locus 2 were common in our study population (minor allele frequency ∼50{\%}, 25{\%} homozygous for risk-associated allele). Analysis of the National Cancer Institute's Cancer Genetic Markers of Susceptibility (CGEMS) prostate cancer association study database alone and in combination with our data provided further evidence for this second prostate cancer risk locus; in the combined analysis, the allele frequencies for rs6983267 differed statistically significantly between case patients and control subjects (P = 1.61 × 10-9). We also identified a third locus at 8q24, approximately 400 kb centromeric to locus 2, that was statistically significantly associated with prostate cancer risk in a combined analysis of our data and CGEMS study data (P = 6.8 × 10-4). A joint analysis of loci 1 and 2 indicated that 35{\%} of the control subjects carried risk genotypes at one or both these loci; compared with men with the nonrisk genotype at both loci, men with risk genotypes at both loci had an odds ratio of prostate cancer of 2.68 (95{\%} confidence interval [CI] = 1.62 to 4.43) and men with risk genotypes at either locus had an odds ratio of prostate cancer of 1.70 (95{\%} CI = 1.39 to 2.07). Conclusions: Three loci at 8q24 are independent genetic risk factors for prostate cancer.",
author = "Zheng, {S. Lilly} and Jielin Sun and Yu Cheng and Ge Li and Hsu, {Fang Chi} and Yi Zhu and Chang, {Bao Li} and Wennuan Liu and Kim, {Jin Woo} and Turner, {Aubrey R.} and Marta Gielzak and Guifang Yan and Isaacs, {Sarah D.} and Wiley, {Kathleen E.} and Jurga Sauvageot and Chen, {Huann Sheng} and Robin Gurganus and Mangold, {Leslie A.} and Bruce Trock and Henrik Gronberg and David Duggan and Carpten, {John D.} and Partin, {Alan Wayne} and Patrick Walsh and Jianfeng Xu and Isaacs, {William B}",
year = "2007",
month = "10",
doi = "10.1093/jnci/djm169",
language = "English (US)",
volume = "99",
pages = "1525--1533",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
publisher = "Oxford University Press",
number = "20",

}

TY - JOUR

T1 - Association between two unlinked loci at 8q24 and prostate cancer risk among European Americans

AU - Zheng, S. Lilly

AU - Sun, Jielin

AU - Cheng, Yu

AU - Li, Ge

AU - Hsu, Fang Chi

AU - Zhu, Yi

AU - Chang, Bao Li

AU - Liu, Wennuan

AU - Kim, Jin Woo

AU - Turner, Aubrey R.

AU - Gielzak, Marta

AU - Yan, Guifang

AU - Isaacs, Sarah D.

AU - Wiley, Kathleen E.

AU - Sauvageot, Jurga

AU - Chen, Huann Sheng

AU - Gurganus, Robin

AU - Mangold, Leslie A.

AU - Trock, Bruce

AU - Gronberg, Henrik

AU - Duggan, David

AU - Carpten, John D.

AU - Partin, Alan Wayne

AU - Walsh, Patrick

AU - Xu, Jianfeng

AU - Isaacs, William B

PY - 2007/10

Y1 - 2007/10

N2 - Background: Recent studies have provided evidence of associations between genetic markers at human chromosome 8q24 and an increased risk of prostate cancer. We examined whether multiple independent risk variants exist in this region and whether the strength of observed associations differs as a function of disease aggressiveness. Methods: We evaluated associations between 18 single-nucleotide polymorphisms (SNPs) in a 1-Mb interval at 8q24 and the risk of prostate cancer among 1563 case patients (1017 of whom had high-grade [Gleason score ≥7] and/or non-organ-confined disease) and 576 control subjects of European American ancestry. Differences in genotype frequencies between case and control subjects were compared using logistic regression analysis, with adjustment for age, and the Wald chi-square test. All statistical tests were two-sided. Results: We identified multiple SNPs in a 50-kb region (referred to as locus 1) that are in linkage disequilibrium with a previously reported risk-associated SNP at 8q24, rs1447295, but were more strongly associated with prostate cancer risk in our study population. We also identified a novel susceptibility SNP, rs6983267, at a second locus (locus 2) that is approximately 70 kb centromeric of rs1447295 and in linkage equilibrium with, and independent of, locus 1. Risk alleles at locus 2 were common in our study population (minor allele frequency ∼50%, 25% homozygous for risk-associated allele). Analysis of the National Cancer Institute's Cancer Genetic Markers of Susceptibility (CGEMS) prostate cancer association study database alone and in combination with our data provided further evidence for this second prostate cancer risk locus; in the combined analysis, the allele frequencies for rs6983267 differed statistically significantly between case patients and control subjects (P = 1.61 × 10-9). We also identified a third locus at 8q24, approximately 400 kb centromeric to locus 2, that was statistically significantly associated with prostate cancer risk in a combined analysis of our data and CGEMS study data (P = 6.8 × 10-4). A joint analysis of loci 1 and 2 indicated that 35% of the control subjects carried risk genotypes at one or both these loci; compared with men with the nonrisk genotype at both loci, men with risk genotypes at both loci had an odds ratio of prostate cancer of 2.68 (95% confidence interval [CI] = 1.62 to 4.43) and men with risk genotypes at either locus had an odds ratio of prostate cancer of 1.70 (95% CI = 1.39 to 2.07). Conclusions: Three loci at 8q24 are independent genetic risk factors for prostate cancer.

AB - Background: Recent studies have provided evidence of associations between genetic markers at human chromosome 8q24 and an increased risk of prostate cancer. We examined whether multiple independent risk variants exist in this region and whether the strength of observed associations differs as a function of disease aggressiveness. Methods: We evaluated associations between 18 single-nucleotide polymorphisms (SNPs) in a 1-Mb interval at 8q24 and the risk of prostate cancer among 1563 case patients (1017 of whom had high-grade [Gleason score ≥7] and/or non-organ-confined disease) and 576 control subjects of European American ancestry. Differences in genotype frequencies between case and control subjects were compared using logistic regression analysis, with adjustment for age, and the Wald chi-square test. All statistical tests were two-sided. Results: We identified multiple SNPs in a 50-kb region (referred to as locus 1) that are in linkage disequilibrium with a previously reported risk-associated SNP at 8q24, rs1447295, but were more strongly associated with prostate cancer risk in our study population. We also identified a novel susceptibility SNP, rs6983267, at a second locus (locus 2) that is approximately 70 kb centromeric of rs1447295 and in linkage equilibrium with, and independent of, locus 1. Risk alleles at locus 2 were common in our study population (minor allele frequency ∼50%, 25% homozygous for risk-associated allele). Analysis of the National Cancer Institute's Cancer Genetic Markers of Susceptibility (CGEMS) prostate cancer association study database alone and in combination with our data provided further evidence for this second prostate cancer risk locus; in the combined analysis, the allele frequencies for rs6983267 differed statistically significantly between case patients and control subjects (P = 1.61 × 10-9). We also identified a third locus at 8q24, approximately 400 kb centromeric to locus 2, that was statistically significantly associated with prostate cancer risk in a combined analysis of our data and CGEMS study data (P = 6.8 × 10-4). A joint analysis of loci 1 and 2 indicated that 35% of the control subjects carried risk genotypes at one or both these loci; compared with men with the nonrisk genotype at both loci, men with risk genotypes at both loci had an odds ratio of prostate cancer of 2.68 (95% confidence interval [CI] = 1.62 to 4.43) and men with risk genotypes at either locus had an odds ratio of prostate cancer of 1.70 (95% CI = 1.39 to 2.07). Conclusions: Three loci at 8q24 are independent genetic risk factors for prostate cancer.

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U2 - 10.1093/jnci/djm169

DO - 10.1093/jnci/djm169

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JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

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