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Finding prostate cancer's chromosomal address

Ostrander, Stanford teams narrow down neighborhood of prostate-cancer susceptibility gene
Dr. Danielle Friedrichsen
Dr. Danielle Friedrichsen prepares DNA samples for microsatellite analysis in the Ostrander lab. The technique was used to map the general location of a prostate-cancer gene. Finding a gene could lead to a genetic test to identify men at increased risk for developing prostate cancer. Photo by Todd McNaught

Center researchers have zeroed in on the neighborhood of a new gene associated with an inherited form of prostate cancer. In an analysis of 36 families in which prostate cancer was prevalent, scientists found that relatives with the disease shared similar DNA sequence patterns on a portion of one of their chromosomes.

Determining the general region of a chromosome linked to the inheritance of increased cancer risk is the first step toward pinpointing an actual cancer-susceptibility gene. Finding a gene could lead to a genetic test to identify men who are more likely than the general population to develop prostate cancer.

In addition to laying the groundwork for the discovery of a new prostate-cancer susceptibility gene, the achievement is significant because numerous previous attempts to find such genes have produced few conclusive results.

To increase their likelihood of success, the researchers focused their analysis exclusively on Ashkenazi Jewish families, a group that tends to be more genetically similar overall compared to the general population because they descend from common ancestors.

Although the study was conducted on a relatively isolated population group, any gene that is ultimately identified could turn out to influence prostate-cancer risk in men of many different ethnic backgrounds.

The study, led by Dr. Danielle Friedrichsen, a postdoctoral fellow in Dr. Elaine Ostrander's lab in the Clinical Research and Human Biology divisions, appears in the Feb. 17 issue of the Proceedings of the National Academy of Sciences. Co-authors at the center were Dr. Janet Stanford, a member the Public Health Sciences Division, Suzanne Kolb, also of PHS, and Ostrander.

A large body of research indicates that about 5 to 10 percent of men who develop prostate cancer come from families in which the disease is prevalent. This suggests that an inherited faulty gene or genes contributed to their risk. Friedrichsen said that the major obstacle to finding genes associated with prostate-cancer risk has been that disease susceptibility comes in many forms.

"There are likely multiple susceptibility genes, and any one group of prostate-cancer families might be enriched for only one of them," she said. "It's like a poker hand, where you are looking for one of many possible 'winning' combinations."

To minimize this difficulty, Friedrichsen said she and her colleagues hypothesized that a population group with common ancestry would be more likely to share the same susceptibility genes, making the search to find them more straightforward. While their work awaits confirmation from additional studies, their hunch appears correct.

"Prostate-cancer families with a common heritage may have increased disease susceptibility due to only one or two genes, which makes a genetic analysis much easier," Friedrichsen said. "Thanks to a collaboration within the International Consortium of Prostate Cancer Genetics, a group that has collected information from families with hereditary prostate cancer, we were able to focus exclusively on a set of Ashkenazi Jewish families for our study."

Family study

Using isolated populations to hunt for disease-susceptibility genes has a history of success. By studying such groups, researchers have identified ancestral mutations in breast-cancer susceptibility genes in Ashkenazi Jews and the gene for Huntington's disease in a large extended Venezuelan family.

For the current study, 36 families who identified themselves as Jewish were culled from two large prostate-cancer research groups: the Fred Hutchinson-based Prostate Cancer Genetic Research Study (PROGRESS), directed by Stanford, and a group at The Johns Hopkins University, directed by Dr. William Isaacs. To be eligible for PROGRESS, families must either have three or more first-degree relatives with prostate cancer, three successive generations with prostate cancer, or two affected men age 65 or younger. For the Johns Hopkins study, families must have at least three first-degree relatives affected. Among the 36 families in this analysis, 149 men had been diagnosed with prostate cancer.

DNA was analyzed, or genotyped, from 161 family members, including 94 affected men. The process involves examining what are known as microsatellite markers, genetic signposts whose physical positions along the chromosome are known. The DNA sequence of each microsatellite marker can vary considerably among individuals.

The Genehunter

When all or most affected individuals within a family inherit identical microsatellite marker sequences on a portion of one of their chromosomes, the markers may help point to the position of a nearby gene which, when mutated, confers elevated risk of the disease. Genotyping data were analyzed in part using a computer program known as Genehunter, developed by Dr. Leonid Kruglyak in the Human Biology Division.

Using this approach, the researchers found that family members with prostate cancer were more likely to inherit identical microsatellite markers on a portion of the long arm of chromosome 7 in a region known as 7q11-21 than would be expected by chance. Previous studies have not linked this genetic neighborhood to prostate-cancer susceptibility.

Friedrichsen is now working to pinpoint the actual gene on chromosome 7 associated with the increased risk of prostate cancer. She and colleagues will analyze the DNA sequences within genes on chromosome 7 to find the mutation that causes prostate-cancer susceptibility in the affected individuals in the Jewish families. It is possible that the same gene may underlie inherited prostate cancer in other populations, although this remains to be tested.

Genetic test

"Upon finding the actual gene, the most immediate goal is a genetic test that would enable men from high-risk families to find out whether they carry the mutation and thereby have an increased susceptible to prostate cancer, which would allow them to be screened regularly for the disease," she said. "Depending on how the gene functions, it also may be a possible target for a drug."

Friedrichsen said that from a basic-research perspective, the gene—depending on its role in the cell—also might illuminate a previously unknown pathway involved in development of prostate cancer, much like the discovery of the BRCA1 and BRCA2 genes revealed a role for DNA repair genes in causing breast cancer.

'Prostate-cancer families with a common heritage may have increased disease susceptibility due to only one or two genes, which makes a genetic analysis much easier.'
Dr. Danielle Friedrichsen, Clinical Research and Human Biology Divisions

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