NEWS

Study Seeks to Clarify Genetic Basis of Prostate Cancer in African Americans

Tom Reynolds

More than 100 African American families have enrolled in a nationwide study to help unravel the genetic basis of prostate cancer, a disease that has disproportionately affected black men.

The African American Hereditary Prostate Cancer (AAHPC) study—taking advantage of the latest genomic resources and technology—is a landmark in several ways. One of the most comprehensive prostate cancer family studies yet, it also offers a model for researchers who seek to recruit African Americans to clinical and genetic studies.

Francis Collins, M.D., Ph.D., director of the National Human Genome Research Institute, said the study, sponsored by NHGRI and the National Cancer Institute, and coordinated by Howard University in Washington, D.C., represents "the most impressive collection of prostate cancer families from any ethnic group."

Medical scientists have long been frustrated by their failure to engage more African Americans in research, a problem due in part, it is believed, to suspicions based on the exploitation of African Americans in the infamous Tuskegee Institute syphilis study. And when the research involves genetics, another whole set of fears about discrimination and misuse of data comes into play.

"Five or six years ago, when people were beginning to chip away at the mysteries of prostate cancer genetics, there were very few African American families" enrolled in research studies, Collins said, "even though that is the population [in which] the disease is particularly dangerous." For the 5-year period ending in 2000, NCI statistics show an average annual prostate cancer incidence of 277 per 100,000 black men, compared with 168 per 100,000 white men. The discrepancy in death rates over the same period is even greater: 73 prostate cancer deaths per 100,000 black men versus 30 per 100,000 white men (see Stat Bite, p. 1357).

A major reason the AAHPC study has succeeded in recruitment is that most leaders of the study, both in the clinic and in the laboratory, are themselves African American.

AAHPC project leader John Carpten, Ph.D., who recently moved his laboratory from NHGRI to the Translational Genomics Research Institute (TGen) in Phoenix, recalled that, when collaborating with researchers at Johns Hopkins University in Baltimore on an earlier prostate cancer genetics study, he was struck and disturbed that only two of 91 participating families were African American.



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Dr. John Carpten

 
"It became obvious to me that one of the most important things in recruitment is gaining trust," Carpten said. He reasoned that trust could best be nurtured in a research project run by African American scientists. Starting in 1997, Carpten, along with Georgia Dunston, Ph.D., director of the National Human Genome Center at Howard University; and Isaac Powell, M.D., associate professor of urology at Wayne State University and chief of urology at the Detroit Veterans Affairs Medical Center, brought together a group of predominantly black scientists and urologists with the aid of the National Medical Association, an African American physician group.

"Concerns about how genetic information might be used against the black community were probably the biggest barrier to recruitment," said Powell, who serves as senior clinical investigator for the AAHPC study. "To overcome the barriers, we tried various methods: churches, newspapers, radio, flyers, social organizations. But the most effective way was through primary care physicians and urologists. Patients trust what their doctor says, because the physician has established a relationship with them." To assuage fears of misuse of data, participants are assured that "blacks have been involved in designing the study, and are in control of the interpretation and publication of the data," he added. "I think that has helped a great deal."

Several Recruitment Sites

In addition to the coordinating center at Howard and Powell’s center at Wayne State’s Karmanos Cancer Institute, other recruitment centers are Midtown Urology in Atlanta, Michael Reese Hospital and Medical Center in Chicago, the University of Texas M. D. Anderson Cancer Center in Houston, Columbia Presbyterian Medical Center in New York, and the University of South Carolina in Columbia.

Each recruitment site also has a study coordinator who follows up with family members, coordinates blood draws, and keeps records of each case, and "they have been absolutely critical to the success of this study," Carpten said. The study’s early recruitment experience is described in the November 2000 Annals of Epidemiology.

Eligible families must have at least four men with prostate cancer, three of whom are alive and available for blood sampling. Their average age at diagnosis must be 65 or younger—a potential indicator of hereditary risk. The investigators collect blood from both the cancer patients and their unaffected relatives, isolate the blood cells’ DNA, then scan the entire genome using genetic markers.

In a genome-wide scan, more than 400 such markers are used, spanning the entire human genome and spaced about 10 million bases apart. Searching for telltale repeat DNA sequences found in prostate cancer patients but not in unaffected relatives, the investigators hope these markers will direct them to specific loci in the genome, which in turn should lead them to the actual gene mutations involved in prostate cancer inheritance. Carpten said the sequencing of the human genome and the broad availability of genome Web browsers now make it far simpler than even a few years ago to find genes that map to the marker regions and that have functions suggesting a potential role in cancer.

Earlier Work

In the 1990s, Carpten and colleagues identified a locus associated with hereditary prostate cancer on chromosome 1, which they dubbed HPC1. In 2002, Carpten’s group found that two families with cancers linked to HPC1 had germline mutations in the RNAse L gene (RNASEL), which lies in the same region of chromosome 1. Reporting the results in the February 2002 Nature Genetics, they suggested that germline mutations in RNASEL may be of diagnostic value, and that the pathway involved might lead to new therapies for prostate cancer. Three independent research groups have published reports suggesting a role for RNASEL in increased prostate cancer risk, Carpten added.

Two other genes associated with hereditary prostate cancer, he said, are ELAC2 (alias HPC2), on chromosome 17, which was discovered by scientists at Myriad Genetics of Salt Lake City, and MSR1 (macrophage scavenger receptor 1) identified by a group at Wake Forest University, Winston-Salem, N.C. University of Michigan researchers recently published a study showing that black men with germline mutations in MSR1 had an increased risk of prostate cancer.

Participants in the AAHPC study are being screened for mutations in these three genes. But Carpten predicts that most families in the study will show linkages to yet other genes.

"There are a lot of data suggesting that there is significant heterogeneity in hereditary prostate cancer," he said.

Powell added that preliminary data show that "the [genomic] sites we have found are different than those that have been reported in the literature."

Carpten said the researchers have completed a genome-wide scan on about half of the 90 families currently collected, and hope to have all collected families completed within the year.

"It’s really exciting because no one has done anything like this before," he said. "We may be able to identify genes that are involved not only in the susceptibility, but also in the aggressiveness of prostate cancer." Such findings could be particularly important for African Americans, who frequently have a more aggressive form of prostate cancer.

Powell noted that the International Consortium of Prostate Cancer Genetics (http://www.icpcg.org), of which the AAHPC study is part, has found data suggesting that several sites in the genome appear to be linked to increased risk for the disease in specific ethnic groups or geographic locations. And although only about 10% to 15% of prostate cancer cases are believed to be hereditary, the study might identify genes that are also involved in sporadic cases, which may also differ by ethnicity.

"This is the most successful example of how we can recruit families with a genetic disorder from the African American population, where there has traditionally been a good deal of skepticism and suspicion about research and genetics," Collins said. "The study has overcome these barriers in large part because the leadership of the project comes from the African American community," a model he suggested other research projects seeking to recruit minorities might emulate.


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