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Genetic Epidemiologist Speaks on DNA Adducts in Prostate Cancer

By Lillian Gu
August 2007

Benjamin A. Rybicki
Genetic epidemiologist Benjamin A. Rybicki (Photo by Eddy Ball)

During a July 10 visit to NIEHS for an extramural grant review, genetic epidemiologist Benjamin A. Rybicki, Ph.D., gave a presentation titled "DNA Adducts as a Marker of Biologically Effective Dose in Prostate Cancer." Among those attending were his grant administrator, Kimberly McAllister, Ph.D., and DERT Acting Director Dennis Lang, Ph.D.

An investigator at the Henry Ford Health Sciences Center, Rybicki has focused on the clinical potential of DNA adduct formation as a biomarker in assessment of cancer risk, recurrence and prognosis, particularly in prostate cancer. "DNA adducts are one of the few biomarkers for exposures directly related to cancer that can be quantified in human cells," Rybicki explained. "Formation is considered to be a necessary, but not sufficient, step to induce carcinogenesis." DNA adducts are especially promising as biomarkers because they occur early in the disease process and may serve as a measurement of how much of a carcinogen is biologically effective in the body.

Rybicki and his colleagues have completed a series of studies on the role of environmental polycyclic aromatic hydrocarbons (PAHs) in carcinogenesis, building upon previous epidemiological evidence of PAH-DNA adduct formation in lymphocytes, especially in occupational studies. "It occurred to me during a review of the literature," he said at the beginning of his talk, "that PAH in DNA adducts could be a very useful marker of exposure."

According to Rybicki, PAHs are large aromatic planar compounds that comprise a class of over 200 chemicals. Their potential role in cancer was first observed in 1775 when British surgeon Sir Percival Pott demonstrated a correlation between exposure to soot and the incidence of scrotal cancer among chimney sweeps. With access to a large number of biopsy samples from men with prostate cancer treated at the Henry Ford Health Sciences Center, Rybicki's team has been able to use immuno-histochemistry to perform large volume studies on tumor and non-tumor prostatic tissue, exploring what role, if any, polymorphisms in genes, such as ones controlling expression of the repair enzymes, may play in tumorigenesis.

While Rybicki's findings are still tentative, intriguing patterns have emerged. He has found, for example, that tumor cells showed significantly lower adduct levels compared with adjacent non-tumor cells. He also determined that PAH-DNA adduct levels in tumor cells were inversely correlated with higher grade primary tumors, large tumor volumes and high prostate-specific antigen (PSA) levels.

Rybicki speculated that tumor cells may have reduced PAH-DNA adduct levels due to their lower levels of cellular differentiation and increased tumor proliferation. He discovered that while repair enzyme gene polymorphisms or PAH exposure alone produced no associations with prostate cancer, looking at the two together uncovered a strong correlation with prostate cancer risk.

With his most recent NIEHS grant, the researcher hopes to expand understanding of the temporal relationship between DNA adducts and prostate cancer development by studying benign prostate specimens. At Henry Ford, Rybicki has access to benign prostate specimens of a racially diverse cohort of 5,197 men. He hopes to determine whether biomarkers of environmental exposure and PAH-DNA adducts are predictive of later prostate cancer development, as well as 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.

A Tentative, but Sobering Caveat for Minority Males and Grilled Meat Lovers

In a recent study, Rybicki experimented with another adduct-forming compound called 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP), a carcinogen formed when boiling, frying and barbecuing that also has been implicated in human prostate cancer. PhIP is a heterocyclic amine in cooked meats that has been demonstrated to be carcinogenic in rat prostate through the formation of DNA adducts. High consumption of grilled red meat has been associated with a higher incidence of prostate cancer in men, and there is a growing body of evidence that prostate carcinogenesis is biologically different in Caucasian and African American men, who may have a higher exposure to meats cooked at high temperatures.

While higher-temperature cooking, such as grilling and barbecuing, increases PhIP formation in both races, differences in metabolism of PhIP by the enzyme SULT1A1 may account for a two-fold greater risk for prostate cancer among African American males compared with Caucasians at comparable enzyme levels. In addition, these biological differences may result in more robust tumor development in African Americans.

Racial differences aside, according to Rybicki, the backyard barbecue, like smoking and occupational exposure, is a preventable risk factor. There is a certain level of PAHs and PhIPs in all food, but cooking, especially at high temperatures, increases levels dramatically.



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