Genome-wide copy-number variation analysis identifies common genetic variants at 20p13 associated with aggressiveness of prostate cancer.

The genetic determinants for aggressiveness of prostate cancer (PCa) are poorly understood. Copy-number variations (CNVs) are one of the major sources for genetic diversity and critically modulate cellular biology and human diseases. We hypothesized that CNVs may be associated with PCa aggressiveness. To test this hypothesis, we conducted a genome-wide common CNVs analysis in 448 aggressive and 500 nonaggressive PCa cases recruited from Johns Hopkins Hospital (JHH1) using Affymetrix 6.0 arrays. Suggestive associations were further confirmed using single-nucleotide polymorphisms (SNPs) that tagged the CNVs of interest in an additional 2895 aggressive and 3094 nonaggressive cases, including those from the remaining case subjects of the JHH study (JHH2), the NCI Cancer Genetic Markers of Susceptibility (CGEMS) Study, and the CAncer of the Prostate in Sweden (CAPS) Study. We found that CNP2454, a 32.3 kb deletion polymorphism at 20p13, was significantly associated with aggressiveness of PCa in JHH1 [odds ratio (OR) = 1.30, 95% confidence interval (CI): 1.01-1.68; P = 0.045]. The best-tagging SNP for CNP2454, rs2209313, was used to confirm this finding in both JHH1 (P = 0.045) and all confirmation study populations combined (P = 1.77 × 10(-3)). Pooled analysis using all 3353 aggressive and 3584 nonaggressive cases showed the T allele of rs2209313 was significantly associated with an increased risk of aggressive PCa (OR = 1.17, 95% CI: 1.07-1.27; P = 2.75 × 10(-4)). Our results indicate that genetic variations at 20p13 may be responsible for the progression of PCa.

[1]  Yusuke Nakamura,et al.  Genome-wide association study identifies five new susceptibility loci for prostate cancer in the Japanese population , 2010, Nature Genetics.

[2]  Gary D Bader,et al.  Functional impact of global rare copy number variation in autism spectrum disorders , 2010, Nature.

[3]  Teri A Manolio,et al.  Genomewide association studies and assessment of the risk of disease. , 2010, The New England journal of medicine.

[4]  Raquel E. Gur,et al.  Strong synaptic transmission impact by copy number variations in schizophrenia , 2010, Proceedings of the National Academy of Sciences.

[5]  Tomas W. Fitzgerald,et al.  Origins and functional impact of copy number variation in the human genome , 2010, Nature.

[6]  Jake K. Byrnes,et al.  Genome-wide association study of copy number variation in 16,000 cases of eight common diseases and 3,000 shared controls , 2010, Nature.

[7]  J. Carpten,et al.  Inherited genetic variant predisposes to aggressive but not indolent prostate cancer , 2010, Proceedings of the National Academy of Sciences.

[8]  Peter Kraft,et al.  Identification of a new prostate cancer susceptibility locus on chromosome 8q24 , 2009, Nature Genetics.

[9]  Kari Stefansson,et al.  Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility , 2009, Nature Genetics.

[10]  Ali Amin Al Olama,et al.  Identification of seven new prostate cancer susceptibility loci through a genome-wide association study , 2009, Nature Genetics.

[11]  H. Grönberg,et al.  Estimation of absolute risk for prostate cancer using genetic markers and family history , 2009, The Prostate.

[12]  B. Trock,et al.  Individual and cumulative effect of prostate cancer risk‐associated variants on clinicopathologic variables in 5,895 prostate cancer patients , 2009, The Prostate.

[13]  Joshua M. Korn,et al.  De Novo Copy Number Variants Identify New Genes and Loci in Isolated, Sporadic Tetralogy of Fallot , 2009, Nature Genetics.

[14]  Sharon J. Diskin,et al.  Copy number variation at 1q21.1 associated with neuroblastoma , 2009, Nature.

[15]  Robert T. Schultz,et al.  Autism genome-wide copy number variation reveals ubiquitin and neuronal genes , 2009, Nature.

[16]  J. Stanford,et al.  Analysis of Recently Identified Prostate Cancer Susceptibility Loci in a Population-based Study: Associations with Family History and Clinical Features , 2009, Clinical Cancer Research.

[17]  Pär Stattin,et al.  Association of a germ-line copy number variation at 2p24.3 and risk for aggressive prostate cancer. , 2009, Cancer research.

[18]  John S. Witte,et al.  Prostate cancer genomics: towards a new understanding , 2009, Nature Reviews Genetics.

[19]  Gonçalo Abecasis,et al.  Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis , 2009, Nature Genetics.

[20]  Joshua M. Korn,et al.  Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs , 2008, Nature Genetics.

[21]  Joshua M. Korn,et al.  Integrated detection and population-genetic analysis of SNPs and copy number variation , 2008, Nature Genetics.

[22]  Thomas W. Mühleisen,et al.  Large recurrent microdeletions associated with schizophrenia , 2008, Nature.

[23]  Tomas W. Fitzgerald,et al.  A robust statistical method for case-control association testing with copy number variation , 2008, Nature Genetics.

[24]  Judy H Cho,et al.  Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease , 2008, Nature Genetics.

[25]  Elaine A. Ostrander,et al.  Multiple Novel Prostate Cancer Predisposition Loci Confirmed by an International Study: The PRACTICAL Consortium , 2008, Cancer Epidemiology Biomarkers & Prevention.

[26]  W. Willett,et al.  Multiple loci identified in a genome-wide association study of prostate cancer , 2008, Nature Genetics.

[27]  Kevin M. Bradley,et al.  Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer , 2008, Nature Genetics.

[28]  Ali Amin Al Olama,et al.  Multiple newly identified loci associated with prostate cancer susceptibility , 2008, Nature Genetics.

[29]  J. Carpten,et al.  Two genome-wide association studies of aggressive prostate cancer implicate putative prostate tumor suppressor gene DAB2IP. , 2007, Journal of the National Cancer Institute.

[30]  Adam S. Kibel,et al.  A common variant associated with prostate cancer in European and African populations , 2007 .

[31]  D. Gudbjartsson,et al.  Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes , 2007, Nature Genetics.

[32]  P. Donnelly,et al.  A new multipoint method for genome-wide association studies by imputation of genotypes , 2007, Nature Genetics.

[33]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[34]  P. Fearnhead,et al.  Genome-wide association study of prostate cancer identifies a second risk locus at 8q24 , 2007, Nature Genetics.

[35]  D. Gudbjartsson,et al.  Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24 , 2007, Nature Genetics.

[36]  Brown Mh,et al.  The SIRP family of receptors and immune regulation. , 2006 .

[37]  Tom H. Pringle,et al.  The human genome browser at UCSC. , 2002, Genome research.

[38]  A. Ullrich,et al.  A family of proteins that inhibit signalling through tyrosine kinase receptors , 1997, Nature.

[39]  Jake K. Byrnes,et al.  Genome-wide association study of copy number variation in 16,000 cases of eight common diseases and 3,000 shared controls , 2010 .

[40]  J. Carpten,et al.  Association of a GermLine Copy Number Variation at 2 p 24 . 3 and Risk for Aggressive Prostate Cancer , 2009 .

[41]  Christian Gieger,et al.  Six new loci associated with body mass index highlight a neuronal influence on body weight regulation , 2009, Nature Genetics.

[42]  K. Mossman.  The Wellcome Trust Case Control Consortium, U.K. , 2008 .

[43]  A. Barclay,et al.  The SIRP family of receptors and immune regulation , 2006, Nature Reviews Immunology.