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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Rundle, Andrew; Wang, Yun; Sadasivan, Sudha et al. (2017) Larger men have larger prostates: Detection bias in epidemiologic studies of obesity and prostate cancer risk. Prostate 77:949-954
Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb et al. (2016) Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation. Nat Commun 7:10979
Han, Ying; Rand, Kristin A; Hazelett, Dennis J et al. (2016) Prostate Cancer Susceptibility in Men of African Ancestry at 8q24. J Natl Cancer Inst 108:
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
Rand, Kristin A; Song, Chi; Dean, Eric et al. (2016) A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci. Cancer Epidemiol Biomarkers Prev 25:1609-1618
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
Helfand, Brian T; Roehl, Kimberly A; Cooper, Phillip R et al. (2015) Associations of prostate cancer risk variants with disease aggressiveness: results of the NCI-SPORE Genetics Working Group analysis of 18,343 cases. Hum Genet 134:439-50
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
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

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