"Silenced" gene suggests greater risk and a possible diagnostic marker for African-Americans with prostate cancer

By Steve Tokar

Rajvir Dahiya, PhD -----

Among African-Americans with prostate cancer, a tumor-suppressing gene called
GSTP1 is inactivated at a rate 3.5 times higher than among Caucasians, according to a study conducted at the San Francisco VA Medical Center (SFVAMC).

“This could be one of the mechanisms for the higher incidence of prostate cancer in African-Americans compared to Caucasians,” said Rajvir Dahiya, PhD, Director of the Urology Research Center at SFVAMC and the principal investigator of the study. “When tumor suppression activity goes down, the tumor progresses much faster.”

In the United States, African-Americans have almost 1.7 times the incidence and mortality of prostate cancer compared to Caucasians (272 per 100,000 vs. 164 per 100,000, respectively).

Researchers found that the GSTP1 gene is temporarily inactivated, or “silenced,” through the process of hypermethylation, in which methyl groups
(CH3) replace hydrogen atoms (H) in cytosine, one of the four protein bases of the gene’s DNA.

The study is the first to investigate and discover ethnic differences in GSTP1 hypermethylation between African-Americans, Caucasians, and Asians. It is being published in the August 20, 2005 issue of the International Journal of Cancer, currently available online.

The researchers noted that “in the African-American population, GSTP1 methylation is a particularly good biomarker” for prostate cancer, since it is more likely to indicate the presence of the disease than in other ethnic groups. Thus, for African-Americans, it is both a potential cause of disease and a tool for diagnosing it, according to Dahiya, who is also a professor of urology at the University of California, San Francisco (UCSF).

Although the researchers gathered their data using pathology samples, GSTP1 can be measured in body fluids. Dahiya says that for African-Americans with high levels of GSTP1 hypermethylation, appropriate treatment strategies would include more aggressive treatment and frequent monitoring.

In the current study, Dahiya and his fellow researchers studied pathology samples from 291 prostate cancer patients (170 Asian, 44 African-American, and
77 Caucasian-American), and compared them with 172 samples (96 Asian, 38 African-American, and 38 Caucasian-American) from patients with benign prostate hypertrophy, or enlarged prostate. All Asian samples were obtained from Shimane University Hospital in Izumo, Japan; all Caucasian and African-American samples were obtained at SFVAMC. From each sample, the researchers took DNA, amplified it using polymerase chain reaction techniques, and looked for reactions indicating the presence of methylation. Through direct DNA sequencing, they then discovered which regions of GSTP1 were methylated.

The study does not explore possible causes for GSTP1 hypermethylation. However, Dahiya noted that the incidence of prostate cancer among Africans in Africa is significantly lower than among African-Americans, and that Asians in Asia have lower rates than Asian-Americans. “That tells us that dietary and environmental factors play a very important role in this disease,” he said.

Dahiya emphasized that the change observed in GSTP1 is epigenetic—a potentially reversible change in gene function—as opposed to a mutation, which is an irreversible change in a gene’s DNA sequencing. In other studies, Dahiya has in fact reactivated GSTP1 by reversing hypermethylation. However, the compound that does this is highly toxic, and researchers are exploring other avenues to accomplish the same result. Soybean products and other foods containing plant estrogens seem particularly promising, noted Dahiya. “In prostate cancers that turn out to be linked to diet, we cannot repair genetic damage,” he said. “But hopefully we can repair epigenetic damage through diet management.”

Dahiya is currently conducting a nationwide study of prostate cancer and hypermethylation rates among much larger samples of Caucasians, Asian-Americans, and African-Americans, “to make this study more valid and stronger.”

Co-investigators include Hideki Enokida, MD, PhD, of SFVAMC, UCSF, and Kagoshima University, Japan; Hiroaki Shiina, MD, PhD, and Shinji Urakami, MD, of SFVAMC, UCSF, and Shimane University, Japan; Mikio Igawa, MD, of Shimane University, Japan; Tatsuya Ogishima, MD, Deepa Pookot, MS, Long-Cheng Li, and Z. Laura Tabatabai, MD, of SFVAMC and UCSF; Motoshi Kawahara, MD, and Masayuki Nakagawa, MD, PhD, of Kagoshima University, Japan; and Christopher J. Kane, MD, and Peter R. Carroll, MD, of SFVAMC and UCSF.

The study was funded by a grant from the National Institutes of Health that was administered by the Northern California Institute for Research and Education (NCIRE), and grants from the U.S. Department of Veterans Affairs.

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