Demetrius Albanes

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Extramural

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PLCO (Learn more about this study)

2005-0018

Apr 21, 2006

Genetic variation in the vitamin E blood transport, cellular uptake, and metabolism pathway and prostate cancer risk

In the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial, we recently found reduced risks for prostate cancer associated with high levels of serum a-tocopherol and for advanced prostate cancer in smokers who used higher doses of supplemental vitamin E (Kirsh et al, JNCI, under review), complimenting results from the ATBC Trial and other epidemiologic studies. With these promising findings, we now propose to examine prostate cancer risk in relation to common single nucleotide polymorphisms (SNPs) and haplotypes in genes that influence vitamin E transport (TTPA, TAP, LPL, PLTP), cellular uptake (LDLR, LRP, SR-B1), efflux (ABCA1), and metabolism (PXR, CYP3A4, CYP3A5, CYP4F2, MDR3) in the PLCO Study. Our project will expand on information gained in the recently PLCO-EEMS approved Cancer Genetic Markers of Susceptibility (C-GEMS) Study, which includes 1,244 prostate cancer cases (826 are incident and 737 are advanced) and 1,158 matched controls. The PLCO C-GEMS gene scan will include SNP coverage of the genome with as many as 300,000 markers, selected to characterize common genetic variation across the entire genome. The data from C-GEMS will likely encompass the major variation in the vitamin E-related genes to be considered in out project, providing substantive information on main effects of selected polymorphisms. We plan to supplement the C-GEMS SNP characterization of each candidate gene, as needed, by including additional nonsynonymous variants (leading to amino acid changes), SNPs in conserved regions of the genes, or SNPs that enhance coverage of the gene regions. This extra coverage can be provided within the DNA allocation already made for the C-GEMS project. Although we may be able to refine the C-GEMS findings with respect to main effects of variants in these genes, our major purpose is to evaluate gene-phenotype relations (baseline serum a- and g-tocopherol data are available) and to explore gene-gene and gene-environment interactions. The results of this project will provide added value to both ongoing and completed work in PLCO regarding the vitamin E - prostate cancer association. Ultimately, characterization of the relation of prostate cancer with common variation in vitamin E regulatory pathways may provide indicators for individual vitamin E supplementation regimens in chemoprevention trials and in the clinical setting.