Study
PLCO
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Project ID
2011-0120
Initial CDAS Request Approval
Aug 11, 2011
Title
Genetic Association of Advanced Prostate Cancer to Fragile Histidine Triad Gene (FHIT)
Summary
Fragile Histidine Triad Gene (FHIT) is composed of 10 short exons spanning an approximately 1.5 Mb region and encodes a 16.8 kD triphosphatase known to promote apoptosis in epithelial cells through the AKT/Survivin pathway. FHIT is also known as a molecular link between carcinogens and several human cancers. Although loss of FHIT protein expression has been associated with metastasis and reduced survival in many types of cancer, we were the first to report a genetic locus of prostate cancer susceptibility within intron 5 of FHIT using a candidate gene-based linkage study and subsequent association tests. Analysis on existing CGEMS data of PLCO prostate cancer and American Cancer Society prostate cancer detected association of aggressive prostate cancer, defined as cases with a Gleason Score > 7 or Stage III & IV, to an independent locus in FHIT and synergistic effect between FHIT and 8q24 (unpublished results). Whether the genetic variants are associated with advanced prostate cancer, defined as those who die from prostate cancer or Gleason Score > 8, or Stage III & IV, remain untested. The existing analyses were also limited by the SNPs included in the Illumina HumanHap300 and 240S arrays, therefore, may have not identified SNPs that functionally underline association to prostate cancer. We propose an analysis of existing and pending GWAS data on PLCO prostate to assess association of advanced prostate cancer to FHIT and synergistic effect between loci in FHIT and 8q24 adjusted for family history of prostate cancer, diabetes, body mass index (BMI), and exposures such as smoking, alcohol, red meats, soy products, and nonsteroidal anti-inflammatory drug (NSAIDs) use.
Aims
Specific Aim 1: Examine association of advanced prostate cancer to SNPs in FHIT. We will test the hypothesis that a genetic locus surrounding exon 5 of FHIT increase risk to advanced prostate cancer using existing GWAS data on PLCO prostate subjects. Specific Aim 2: Verify interaction between SNPs in FHIT and 8q24 for their association to advanced prostate cancer. The hypothesis is that genetic loci in FHIT and 8q24 function synergistically to promote a man's risk to advanced prostate cancer. Specific Aim 3: Explore interaction between genotypes of FHIT and exposure variables, such as smoking and red meat consumption. We hypothesize that carcinogen and/or dietary exposures modify risk of advanced prostate cancer through FHIT function. Specific Aim 4: Refine genetic loci in FHIT using GWAS data from Illumina HumanOmini2.5-Quad array. The underlining hypothesis is that additional partially linked SNPs truly define prostate cancer risk.
Collaborators
Almanda Black (NCI)
Ann Hsing (NCI)
