Prostate Cancer is a slow growing disease that likely involves a series of environmental insults resulting in accumulated DMA damage eventually leading to overt carcinogenesis. DNA adducts are one of the few biomarkers for exposures directly related to cancer that can be quantified in human cells and a reliable measure of biologically effective dose for known carcinogens such as polycyclic aromatic hydrocarbons (PAH) and 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP). Epigenetic markers are emerging as important in determining the extent of prostate carcinogenesis. Recent studies suggest that DNA adduct formation and aberrant gene promoter hypermethylation may be related elements in environmentally-induced carcinogenesis. Most research done with respect to DNA adducts, promoter hypermethylation and prostate cancer has focused on cells harvested from patients with prostate cancer or pre-malignant lesions. While these studies have been instructive, a clearer picture of the interconnection and risk associated with DNA adduct formation and epigenetic changes in prostate can only be gained from studies of prostate tissue captured before the onset of disease. At the Henry Ford Health System, we have characterized and have access to a racially diverse cohort of over five thousand men without prostate cancer from whom benign prostate specimens were surgically removed between 1990 and 2002. We plan to expand this cohort through 2006, and will follow-up cohort members for incident prostate cancer diagnoses through 2010 to achieve a desired study sample size of 800 matched case-control pairs. Building on findings from our initial funding period that characterized determinants of PAH- and PhlP-DNA adducts in the prostate cells of men with prostate cancer, in this competing continuation we seek to better understand the temporal relationship between DNA adducts and other epigenetic changes in the benign prostate and later prostate cancer development. To achieve this objective, we plan to conduct a nested case-control study of prostate cancer that will: 1) determine whether PAH- and PhlP-DNA adducts are predictive of later prostate cancer development after adjusting for other possible confounders;2) determine in a multivariable model how aberrant gene promoter DNA methylation affects the association between PAH-and PhlP-DNA adducts and prostate cancer;and 3) determine whether DNA adducts in the benign prostate are associated with the level of expression of the p53 and p21waf/cip1 tumor suppressor genes in prostate tumors of men who develop prostate cancer.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Special Emphasis Panel (ZRG1-HOP-N (02))
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Mcallister, Kimberly A
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Henry Ford Health System
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Rybicki, Benjamin A; Rundle, Andrew; Kryvenko, Oleksandr N et al. (2016) Methylation in benign prostate and risk of disease progression in men subsequently diagnosed with prostate cancer. Int J Cancer 138:2884-93
Rybicki, B A; Kryvenko, O N; Wang, Y et al. (2016) Racial differences in the relationship between clinical prostatitis, presence of inflammation in benign prostate and subsequent risk of prostate cancer. Prostate Cancer Prostatic Dis 19:145-50
Rand, Kristin A; Rohland, Nadin; Tandon, Arti et al. (2016) Whole-exome sequencing of over 4100 men of African ancestry and prostate cancer risk. Hum Mol Genet 25:371-81
Han, Ying; Signorello, Lisa B; Strom, Sara S et al. (2015) Generalizability of established prostate cancer risk variants in men of African ancestry. Int J Cancer 136:1210-7
Han, Ying; Hazelett, Dennis J; Wiklund, Fredrik et al. (2015) Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions. Hum Mol Genet 24:5603-18
Barber, Alison G; Castillo-Martin, Mireia; Bonal, Dennis M et al. (2015) PI3K/AKT pathway regulates E-cadherin and Desmoglein 2 in aggressive prostate cancer. Cancer Med 4:1258-71
Kataria, Yachana; Wright, Margaret; Deaton, Ryan J et al. (2015) Dietary influences on tissue concentrations of phytanic acid and AMACR expression in the benign human prostate. Prostate 75:200-10
Zaitlen, Noah; Pasaniuc, Bogdan; Sankararaman, Sriram et al. (2014) Leveraging population admixture to characterize the heritability of complex traits. Nat Genet 46:1356-62
Barber, Alison G; Castillo-Martin, Mireia; Bonal, Dennis M et al. (2014) Characterization of desmoglein expression in the normal prostatic gland. Desmoglein 2 is an independent prognostic factor for aggressive prostate cancer. PLoS One 9:e98786
Al Olama, Ali Amin; Kote-Jarai, Zsofia; Berndt, Sonja I et al. (2014) A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat Genet 46:1103-9

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