Genetics of Prostate Cancer Risk & Agressiveness

Summary

Principal Investigator: Graham Casey
Abstract: We hypothesize that multiple genes are involved in risk of prostate cancer and tumor aggressiveness and that many of these genetic risk factors will be represented by low penetrance gene mutations, each accounting for a small effect on risk. We propose to build upon two promising areas of our research program concerned with the influence of genes on prostate cancer risk and tumor aggressiveness. We have localized prostate tumor aggressiveness genes to 7q32-q33 and 19q13.1 through whole genome linkage analysis of sib pairs and loss of heterozygosity studies. We have identified a strong candidate, podocalyxin (PODXL), on 7q32-q33 in which in-frame deletions and SNPs independently are associated with markers of tumor aggressiveness. We will also build upon our studies investigating the impact of single nucleotide polymorphisms (SNPs) in candidate genes involved in metabolic pathways involved in prostate growth on prostate cancer risk and tumor aggressiveness. Thus our Specific Aims are: Specific Aim 1: To further characterize candidate prostate tumor aggressiveness loci identified through whole genome linkage analysis. We will determine whether PODXL functions as a prostate tumor aggressiveness gene by developing stable transfectants expressing wild-type or variant-containing PODXL and assessing their effect on in vitro and in vivo growth of prostate cancer cells. We will also determine PODXL expression in prostate tumors by in situ hybridization and immunohistochemical staining using tissue microarrays. We will further pursue the identification of the 19q13.1 aggressiveness gene using complementary approaches, including positional cloning methods and use of the public Human Genome Project (HGP) and Celera databases. The relationship between the 19q13.1 candidate gene(s) and prostate tumor aggressiveness will be evaluated by mutation analyses followed by association studies. Candidates will be further evaluated by in situ hybridization and immunohistochemical staining. Specific Aim 2: To determine the impact of single nucleotide polymorphisms (SNPs) in candidate genes on prostate cancer risk and tumor aggressiveness. We will study SNPs in candidate genes involved in 1) vitamin D metabolism (vitamin D receptor, 1-alpha-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24)), 2) insulin-like growth factor signaling (IGFBP-3), 3) folate metabolism (5,10- Methylene-tetrahydrofolate reductase (MTHFR) and Methionine Synthase (MTR)), and 4) steroid hormone metabolism (CYP3A7). For SNP association studies, we will employ a fully recruited population consisting of 943 men in 431 families with at least one brother affected with prostate cancer. Epidemiologic and clinical data have been collected, as well as biospecimens and banked DNA. The relationship between these genetic factors and prostate cancer risk and aggressiveness will be statistically evaluated.
Funding Period: 2003-09-12 - 2010-06-30
more information: NIH RePORT

Top Publications

  1. pmc Impact of consumption of vegetable, fruit, grain, and high glycemic index foods on aggressive prostate cancer risk
    Jill Hardin
    Department of Epidemiology, University of California at San Francisco, San Francisco, California 94158 9001, USA
    Nutr Cancer 63:860-72. 2011
  2. pmc Fine-mapping of prostate cancer aggressiveness loci on chromosome 7q22-35
    Xin Liu
    Mary Ann and J Milburn Smith Child Health Research Program, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
    Prostate 71:682-9. 2011
  3. pmc Prostate cancer susceptibility variants confer increased risk of disease progression
    Iona Cheng
    Epidemiology Program, Cancer Research Center of Hawai i, University of Hawai i, Honolulu, Hawaii, USA
    Cancer Epidemiol Biomarkers Prev 19:2124-32. 2010
  4. pmc Dietary omega-3 fatty acids, cyclooxygenase-2 genetic variation, and aggressive prostate cancer risk
    Vincent Fradet
    Departments of Urology, Institute for Human Genetics, University of California at San Francisco, San Francisco, California 94143 0794, USA
    Clin Cancer Res 15:2559-66. 2009
  5. pmc Carboxypeptidase 4 gene variants and early-onset intermediate-to-high risk prostate cancer
    Phillip L Ross
    Department of Urology, University of California San Francisco, San Francisco, CA, USA
    BMC Cancer 9:69. 2009
  6. ncbi Pathological aggressiveness of prostatic carcinomas related to RNASEL R462Q allelic variants
    Benjamin T Larson
    Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio, USA
    J Urol 179:1344-8. 2008
  7. pmc 8q24 and prostate cancer: association with advanced disease and meta-analysis
    Iona Cheng
    Department of Epidemiology and Biostatistics and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143 0794, USA
    Eur J Hum Genet 16:496-505. 2008
  8. ncbi Podocalyxin increases the aggressive phenotype of breast and prostate cancer cells in vitro through its interaction with ezrin
    Steven Sizemore
    Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    Cancer Res 67:6183-91. 2007
  9. pmc COX2 genetic variation, NSAIDs, and advanced prostate cancer risk
    I Cheng
    Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94143 0794, USA
    Br J Cancer 97:557-61. 2007
  10. ncbi MIC1 and IL1RN genetic variation and advanced prostate cancer risk
    Iona Cheng
    Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94143 0794, USA
    Cancer Epidemiol Biomarkers Prev 16:1309-11. 2007

Scientific Experts

  • John Witte
  • Phillip L Ross
  • Graham Casey
  • Xin Liu
  • Iona Cheng
  • Sarah J Plummer
  • Mine S Cicek
  • Nora L Nock
  • Benjamin A Rybicki
  • Eric Jorgenson
  • Jill Hardin
  • Vincent Fradet
  • Eric A Klein
  • Benjamin T Larson
  • I Cheng
  • Steven Sizemore
  • Fredrick R Schumacher
  • Li Li
  • Brian K Suarez
  • William J Catalona
  • Christine Neslund-Dudas
  • Cristina Magi-Galluzzi
  • Robert Silverman
  • Kwok Peng Ng
  • Nywana Sizemore
  • X Liu
  • S J Plummer
  • G Casey
  • Lisa M Krumroy
  • L M Krumroy
  • Muzaffer Cicek
  • Gregory T MacLennan
  • Andrea Moreira
  • Flavius Macarie

Detail Information

Publications17

  1. pmc Impact of consumption of vegetable, fruit, grain, and high glycemic index foods on aggressive prostate cancer risk
    Jill Hardin
    Department of Epidemiology, University of California at San Francisco, San Francisco, California 94158 9001, USA
    Nutr Cancer 63:860-72. 2011
    ..02). These results were driven by a number of specific foods within the food groups. Our findings support the hypothesis that diets high in vegetables and low in high glycemic index foods decrease risk of aggressive prostate cancer...
  2. pmc Fine-mapping of prostate cancer aggressiveness loci on chromosome 7q22-35
    Xin Liu
    Mary Ann and J Milburn Smith Child Health Research Program, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
    Prostate 71:682-9. 2011
    ..To further clarify this finding and focus on the potentially causative gene, we undertook a fine-mapping study across the 7q22-35 region...
  3. pmc Prostate cancer susceptibility variants confer increased risk of disease progression
    Iona Cheng
    Epidemiology Program, Cancer Research Center of Hawai i, University of Hawai i, Honolulu, Hawaii, USA
    Cancer Epidemiol Biomarkers Prev 19:2124-32. 2010
    ..Genome-wide association studies have identified numerous single nucleotide polymorphisms (SNP) associated with the risk of prostate cancer. Our objective was to determine whether these SNPs affect the progression of prostate cancer...
  4. pmc Dietary omega-3 fatty acids, cyclooxygenase-2 genetic variation, and aggressive prostate cancer risk
    Vincent Fradet
    Departments of Urology, Institute for Human Genetics, University of California at San Francisco, San Francisco, California 94143 0794, USA
    Clin Cancer Res 15:2559-66. 2009
    ..This potential effect may be modified by genetic variation in cyclooxygenase-2 (COX-2), a key enzyme in fatty acid metabolism and inflammation...
  5. pmc Carboxypeptidase 4 gene variants and early-onset intermediate-to-high risk prostate cancer
    Phillip L Ross
    Department of Urology, University of California San Francisco, San Francisco, CA, USA
    BMC Cancer 9:69. 2009
    ..We examined the association between genetic variation in CPA4 and intermediate-to-high risk prostate cancer...
  6. ncbi Pathological aggressiveness of prostatic carcinomas related to RNASEL R462Q allelic variants
    Benjamin T Larson
    Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio, USA
    J Urol 179:1344-8. 2008
    ..We assessed a series of men undergoing radical prostatectomy for clinical and pathological measures of tumor aggressiveness according to the RNASEL R462Q genotype...
  7. pmc 8q24 and prostate cancer: association with advanced disease and meta-analysis
    Iona Cheng
    Department of Epidemiology and Biostatistics and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143 0794, USA
    Eur J Hum Genet 16:496-505. 2008
    ..Our findings provide the first confirmation that the three 8q24 regions independently influence the risk of prostate cancer and, in particular, advanced disease...
  8. ncbi Podocalyxin increases the aggressive phenotype of breast and prostate cancer cells in vitro through its interaction with ezrin
    Steven Sizemore
    Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    Cancer Res 67:6183-91. 2007
    ....
  9. pmc COX2 genetic variation, NSAIDs, and advanced prostate cancer risk
    I Cheng
    Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94143 0794, USA
    Br J Cancer 97:557-61. 2007
    ..67; 95% CI: 0.52-0.87). No significant statistical interaction between NSAID use and rs2745557 was observed (P=0.12). Our findings suggest that variation in COX2 is associated with prostate cancer risk...
  10. ncbi MIC1 and IL1RN genetic variation and advanced prostate cancer risk
    Iona Cheng
    Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94143 0794, USA
    Cancer Epidemiol Biomarkers Prev 16:1309-11. 2007
  11. ncbi Toll-like receptor 4 genetic variation and advanced prostate cancer risk
    Iona Cheng
    Department of Epidemiology and Biostatistics and Center of Human Genetics, University of California at San Francisco, 94143 0794, USA
    Cancer Epidemiol Biomarkers Prev 16:352-5. 2007
    ..006). We estimated through permutation analysis that a similarly strong result would occur by chance 2.5% of the time. Our findings support previous studies and suggest that inherited differences in TLR4 influence prostate cancer risk...
  12. ncbi Association of testis derived transcript gene variants and prostate cancer risk
    Xin Liu
    Department of Epidemiology and Biostatistics, and Institute for Human Genetics, University of California, San Francisco, San Francisco, California 94143 0794, USA
    J Urol 177:894-8. 2007
    ..To investigate this concept we evaluated the effects of 7 tagging single nucleotide polymorphisms that comprehensively captured the common genetic variants in TES on aggressive prostate cancer in a case-control study...
  13. ncbi Trans-fatty acid intake and increased risk of advanced prostate cancer: modification by RNASEL R462Q variant
    Xin Liu
    Department of Epidemiology and Biostatistics and Institute for Human Genetics, University of California, San Francisco, CA 94143 0794, USA
    Carcinogenesis 28:1232-6. 2007
    ..This suggests that among Caucasians, positive association between higher trans-fatty acid consumption and prostate cancer may be modified by the functional RNASEL variant R462Q...
  14. ncbi Vitamin D receptor genotypes/haplotypes and prostate cancer risk
    Mine S Cicek
    Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Ohio, USA
    Cancer Epidemiol Biomarkers Prev 15:2549-52. 2006
    ..This would help explain the somewhat equivocal results for VDR genotype-level associations with prostate cancer...
  15. ncbi Nonsteroidal antiinflammatory drugs and decreased risk of advanced prostate cancer: modification by lymphotoxin alpha
    Xin Liu
    Department of Epidemiology and Biostatistics and Center for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA
    Am J Epidemiol 164:984-9. 2006
    ..30). The authors observed similar associations when examining dose/duration of NSAID use. This suggests that any potential chemoprevention of prostate cancer by NSAIDs may be most appropriate for men with the LTA +80CC genotype...
  16. ncbi Polymorphisms in polycyclic aromatic hydrocarbon metabolism and conjugation genes, interactions with smoking and prostate cancer risk
    Nora L Nock
    Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA
    Cancer Epidemiol Biomarkers Prev 15:756-61. 2006
    ..95; 95% CI, 0.53-1.71). Our results highlight the importance of considering genetic modifiers of carcinogens when evaluating smoking in prostate cancer...
  17. ncbi Polymorphisms in estrogen bioactivation, detoxification and oxidative DNA base excision repair genes and prostate cancer risk
    Nora L Nock
    Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA
    Carcinogenesis 27:1842-8. 2006
    ....