Variants in the HEPSIN gene are associated with prostate cancer in men of European origin

There is considerable evidence that genetic factors are involved in prostate cancer susceptibility. We have studied the association of 11 single nucleotide polymorphisms (SNPs) in the HEPSIN gene (HPN) with prostate cancer in men of European ancestry. HPN is a likely candidate in prostate cancer susceptibility, as it encodes a transmembrane cell surface serum protease, which is overexpressed in prostate cancer; HPN is also located on 19q11–q13.2, where linkage is found with prostate cancer susceptibility. In this case-control association study (590 men with histologically verified prostate cancer and 576 unrelated controls, all of European descent), we find significant allele frequency differences between cases and controls at five SNPs that are located contiguously within the gene. A major 11-locus haplotype is significantly associated, which provides further support that HPN is a potentially important candidate gene involved in prostate cancer susceptibility. Association of one of the SNPs with Gleason score is also suggestive of a plausible role of HPN in tumor aggressiveness.

[1]  S. Dhanasekaran,et al.  Delineation of prognostic biomarkers in prostate cancer , 2001, Nature.

[2]  J. Witte,et al.  A genome screen of multiplex sibships with prostate cancer. , 2000, American journal of human genetics.

[3]  Jeffrey A. Magee,et al.  Expression profiling reveals hepsin overexpression in prostate cancer. , 2001, Cancer research.

[4]  A. Jemal,et al.  Cancer Statistics, 2006 , 2006, CA: a cancer journal for clinicians.

[5]  T. Stamey,et al.  Hepsin and maspin are inversely expressed in laser capture microdissectioned prostate cancer. , 2003, The Journal of urology.

[6]  P. Carroll,et al.  20-year outcomes following conservative management of clinically localized prostate cancer , 2005 .

[7]  P. Donnelly,et al.  A new statistical method for haplotype reconstruction from population data. , 2001, American journal of human genetics.

[8]  S. Loening,et al.  Hepsin is highly over expressed in and a new candidate for a prognostic indicator in prostate cancer. , 2004, The Journal of urology.

[9]  D V Conti,et al.  Genomewide scan for prostate cancer-aggressiveness loci. , 2000, American journal of human genetics.

[10]  W. Catalona,et al.  TGFBR1*6A is not associated with prostate cancer in men of European ancestry , 2005, Prostate Cancer and Prostatic Diseases.

[11]  Yogendra P. Chaubey Resampling-Based Multiple Testing: Examples and Methods for p-Value Adjustment , 1993 .

[12]  W. Catalona,et al.  Analysis of Candidate Genes for Prostate Cancer , 2004, Human Heredity.

[13]  A. Hartmann,et al.  Multiple mutation analyses in single tumor cells with improved whole genome amplification. , 1999, The American journal of pathology.

[14]  A. Whittemore,et al.  A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics. , 2005, American journal of human genetics.

[15]  T. Beaty,et al.  Fundamentals of Genetic Epidemiology , 1993 .

[16]  R. Chakraborty,et al.  Whole-genome amplification: relative efficiencies of the current methods. , 2005, Legal medicine.

[17]  J. Witte,et al.  Prostate cancer aggressiveness locus on chromosome segment 19q12–q13.1 identified by linkage and allelic imbalance studies , 2003, Genes, chromosomes & cancer.

[18]  Debashis Ghosh,et al.  Prostate Cancer Expression Profiles Reveals Pathway Dysregulation in Meta-Analysis of Microarrays : Interstudy Validation of Gene Updated , 2002 .

[19]  Li Jin,et al.  Genome amplification of single sperm using multiple displacement amplification , 2005, Nucleic acids research.

[20]  T. Stamey,et al.  Molecular genetic profiling of Gleason grade 4/5 prostate cancers compared to benign prostatic hyperplasia. , 2001, The Journal of urology.

[21]  M. Boehnke,et al.  Allele frequency estimation from data on relatives. , 1991, American journal of human genetics.

[22]  J. Kaprio,et al.  Genetic Susceptibility to Prostate, Breast, and Colorectal Cancer among Nordic Twins , 2005, Biometrics.

[23]  J. Witte,et al.  Replication linkage study for prostate cancer susceptibility genes , 2000, The Prostate.

[24]  J. Witte,et al.  Model-free linkage analysis with covariates confirms linkage of prostate cancer to chromosomes 1 and 4. , 2001, American journal of human genetics.

[25]  K. Lange,et al.  Programs for pedigree analysis: Mendel, Fisher, and dGene , 1988, Genetic epidemiology.

[26]  J. Witte,et al.  Genome‐wide scan of brothers: Replication and fine mapping of prostate cancer susceptibility and aggressiveness loci , 2003, The Prostate.

[27]  S. S. Young,et al.  Resampling-Based Multiple Testing: Examples and Methods for p-Value Adjustment , 1993 .

[28]  S. Reed,et al.  Identification of differentially expressed genes in human prostate cancer using subtraction and microarray. , 2000, Cancer research.

[29]  Peter H. Westfall,et al.  Testing Association of Statistically Inferred Haplotypes with Discrete and Continuous Traits in Samples of Unrelated Individuals , 2002, Human Heredity.

[30]  J. Kaprio,et al.  Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. , 2000, The New England journal of medicine.

[31]  P. Humphrey,et al.  The early detection of prostate carcinoma with prostate specific antigen , 1997, Cancer.

[32]  Perspective: prostate cancer susceptibility genes. , 2002, Endocrinology.