Zeroing in on Chromosome 8: A Hotspot for Genetic Risk Factors
What is it about chromosome 8 that makes it such a bad neighborhood for prostate cancer? William B. Isaacs, Ph.D., who has been scrutinizing this area, has found many genetic risk factors. Mysteriously, “although we have found multiple genetic variants in this region, none of these actually resides within a gene,” says Isaacs, the William Thomas Gerrard, Mario Anthony Duhon and Jennifer and John Chalsty Professor of Urology. So how do these factors raise a man’s risk of developing prostate cancer? One possibility is that the errant gene may be close, but not right next door, to the trouble spots that have been pinpointed. “We are especially interested in one gene that is nearby — the C-MYC gene — for two reasons,” says Isaacs. “We know that in mice, over-expression of this gene causes prostate cancer.
In mice, over-expression of this
gene causes prostate cancer.
Also, Angelo De Marzo’s lab has shown that C-MYC is over-expressed very early in many human prostate cancers, and this may be observed even in some cells that appear normal, but then become cancerous.” Using tissue samples from men who carry the risk variants in one particular region of Chromosome 8, called 8q24, Isaacs and colleagues are looking at the levels of C-MYC in both normal and early prostate cancer cells. “It’s possible that in some men, these variants can increase or otherwise disrupt the expression of C-MYC in prostate cells, and that this can increase their chance of developing cancer.” (For more on C-MYC, click here.) In other news, the National Cancer Institute has awarded an additional five years of support to the International Consortium for Prostate Cancer Genetics Study, which is led by Isaacs.
The study involves more than 65 investigators from around the world who are interested in the inherited susceptibility of prostate cancer. “Together, we have collected more than 2,500 families with three or more first-degree relatives affected with prostate cancer,” reports Isaacs. Using linkage analysis to study these families, “we have identified regions of chromosomes 6, 11 and 20 which may harbor genetic variants that increase a man’s risk of developing an aggressive prostate cancer. We are actively pursuing these regions to identify the specific genes responsible for this inherited risk.”
Why Chromosome 8?
Last year, researchers in Iceland reported that a small region on the long arm of chromosome 8 harbored a genetic variant associated with an increased risk for prostate cancer. William Isaacs and colleagues were able to confirm this observation, “which is significant, because results in this field have been notoriously difficult to reproduce,” Isaacs notes. “Also, we discovered multiple independent genetic variants in the 8q24 region (of Chromosome 8), which are associated in an additive fashion with an increased risk for prostate cancer.” Isaacs’ research indicates that trouble spots in this region account for much of the genetic risk for prostate cancer.
“One of the variants we identified at 8q24 is particularly important in affecting risk for prostate cancer in African Americans,” a group that is particularly hard-hit by prostate cancer.