HOXB13: Indeed a Major Susceptibility Gene for 

Prostate Cancer      


Some people are born with the tendency to develop cancer. For example, a woman’s risk for breast cancer is greatly increased when she inherits a damaged copy of the genes, BRCA1 or BRCA2. And now we know, thanks to the work of William Isaacs, Ph.D., and colleagues, that when a man inherits a mutated form of a gene called HOXB13 (which is important in normal prostate development), his chances of developing prostate cancer are greatly increased.

"Why are these men more likely
to die from prostate cancer? One
reason may be the early onset; the
disease may be at its most curable
when men are in their forties, long
before most men start thinking
about prostate cancer."

Doctors and scientists have known for many years that prostate cancer runs in some families, and that for men in these families, prostate cancer seems to develop sooner than it does in other men. But "uncovering the molecular basis for an inherited form of this disease has been challenging," says Isaacs, the William Thomas Gerrard, Mario Anthony Duhon and Jennifer and John Chalsty Professor of Urology. Last year, in a genetic study of families with prostate cancer, Isaacs and colleagues at the University of Michigan identified a rare mutation of HOXB13, called G84E, is present in men with a family history of prostate cancer who develop the disease at a younger age. Since those findings were published, nine independent studies have confirmed that HOXB13 is a prostate cancer susceptibility gene. Studies from the International Consortium for Prostate Cancer Genetics, the largest collection of hereditary prostate cancer families in the world, and separate analyses of individual study populations, all have reported that men who inherit the G84E form of the gene have a higher likelihood of developing prostate cancer, with increases in risk ranging from four- to 16-fold.

"The G84E version is most common in the populations of Northern Europe and the Nordic countries – areas that have some of the highest rates of deaths from prostate cancer worldwide," notes Isaacs. Why are these men more likely to die from prostate cancer? One reason may be the early onset; the disease may be at its most curable when men are in their forties, long before most men start thinking about prostate cancer.

Additional genetic analyses revealed that all of those carrying this mutation shared a "common founder origin" – that is, they share a common ancestor. In Sweden and Finland, about one in 10 men with early onset, familial prostate cancer carries the G84E mutation. Interestingly, a different recurrent mutation in the HOXB13 gene, called G135E, is linked to a higher prostate cancer risk in Chinese men. "All of these studies clearly show that for prostate cancer, similar to BRCA1 and -2 for breast cancer, HOXB13 is a consistent and strong risk factor," says Isaacs. "These confirming studies emphasize the need for further research so that we can understand the mechanisms responsible for this inherited risk, and begin to translate this information to the clinic."

With support from the Patrick C. Walsh Prostate Cancer Research Fund, Isaacs, who is the Dr. and Mrs. Peter S. Bing Scholar, is using DNA sequencing technology to determine whether there are any other mutated forms of the HOXB13 gene. He is also looking for mutations of other genes in the same neighborhood – genes called PRAC and PRAC2 – to see whether they lead to a higher risk of prostate cancer. "We are looking for these mutations in men of European descent, as well as in the understudied, high-risk population of men of African descent," Isaacs explains. "We hope that identifying and characterizing these mutated genes will help us understand why some men develop prostate cancer. We also hope that our findings will lead to new tests to identify these men at higher risk, as well as for potentially new ways to treat or maybe even prevent prostate cancer."

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