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Differences in cancer rates and experiences between ethnicities may help isolate other genes involved in a particular cancer. Take prostate cancer, for instance. More than 30,000 men died of the disease last year, and nearly 200,000 will be diagnosed this year, according to the American Cancer Society. The incidence of prostate cancer is substantially higher among African-American men than among male Caucasians, and the death rate among blacks is twice that of whites with the same diagnosis.
USC researchers found African-American and Latino men who carry a simple genetic mutation have five times the risk of developing prostate cancer than do men without the mutation.
This is the first mutation directly associated with prostate cancer, says molecular biologist and biochemist Juergen Reichardt of USCs Institute for Genetic Medicine. There have been hints and suggestions before, but this study really spells it out.
When they find a gene that may signal cancer risk, researchers still cant be sure what role changes from the environment or somatic mutations play. Even the most specific genetic tests, like those for BRCA-1 and BRCA-2, are not absolutely definitive, notes Jones. Not everyone who has the gene will develop cancer.
One gene, SRD5A2, codes for an enzyme found in the prostate called steroid 5alpha-reductase, which controls the activation of testosterone that is, its metabolism into dihydrotestosterone, or DHT, which is some 10 to 50 times more powerful than testosterone. Indeed, it is the most potent androgen in the human body. One small mutation in the gene SRD5A2 and, all of a sudden, men begin making buckets of DHT, and their prostate grows faster, says Reichardt.
How the extra DHT results in prostate cancer, however, is still unknown. Reichardt believes the gene may interact with other mutations caused by environmental factors to turn a predisposition to the disease into the disease itself.
Less than 1 percent of normal, healthy men carry the SRD5A2 mutation. However, among African-American and Latino men with prostate cancer, the rate of mutation can rise as high as 10 percent. (The researchers also looked at Asian and Caucasian men, but the link between the mutation and prostate cancer wasnt as clear in these groups.)
The genetics of prostate cancer is somewhat controversial, says Reichardt. But we need to figure out the interplay of the different genetic changes that occur in the predisposition or progression of the disease. The one thing I know is that this wont be the only [cancer-causing] gene discovered. Its sure to be the first of many.
The search for the specific mutations that predict an individuals cancer risk is sped along by technological advances. One of the most helpful tools is a relatively new technology: micro-array scanners. USC biochemist Joe Hacia uses nucleic acid micro-arrays pieces of glass the size of a thumbnail with thousands of DNA sequences imprinted on their surfaces, also called DNA chips to scan for abnormalities in DNA collected from tumor tissue or blood samples. Short pieces of DNA called oligonucleotides are present on the chip surface. More than 250,000 different oligonucleotides can be arrayed on the surface of the glass in a checkerboard pattern.
The manufacturing processes are very similar to those used to create computer microprocessor chips, says Hacia, who also works out of USCs Institute for Genetic Medicine. The whole process, he explains, means comparisons that used to take years can now be completed in a few months.
By screening for mutations in specific genes, Hacia hopes to differentiate, say, one case of lymphoma from another, then correlate mutation status with responsiveness to chemotherapy. Hes currently working with clinicians at the USC/ Norris on mutations associated with lymphomas, leukemias and breast and colon cancers. In the next few years he expects to develop different types of cancer-related chips to screen for cancer mutations.
The field is so broad and has so many opportunities, says Hacia. Were just beginning to tap the power of new technologies.
The grant allows Brian Henderson, a professor of preventive medicine, to expand his Hawaii/Los Angeles Multiethnic Cohort Study (MEC) to include genetic samples. MEC is a prospective study of four racial groups that looks at the ways ethnicity, diet and other environmental factors determine a persons cancer risk. With 215,000 participants, it is the only study of its kind.
The scientific thrust has gone way outside the original box, says Henderson, who is also director of the Keck Schools Neurogenetic Institute. Until now, he explains, searching for genes that have an impact on cancer relied on the use of candidate genes ones that scientists had already tagged as likely players in the diseases pathway. But that tack will only take us so far, Henderson believes.
It will clearly be necessary to screen many genes to find the few that influence each cancer, and to sift through the many polymorphisms that exist in each gene, he says. We were originally looking at a single variant in five or six candidate genes; now were looking at a much larger number of genes with many, many more variants.
Photo by S. Peter Lopez