The James Buchanan Brady Urological Institute
   Hereditary Prostate Cancer Risk: A Major Gene Mutation Is Found
                                                                                                                                              Volume 9, Winter 2013

Johns Hopkins Medicine
Scientists William Isaacs, right, and Charles Ewing
found that men who inherit the HOX B13 mutation
are 10 to 20 times more likely to get prostate cancer
than other men, and at a younger age.
Bill Isaacs might not have imagined it would take more than 20 years, but he knew he was in for a long, tough haul when he started searching for genetic links to cancer in families that had been devastated by prostate cancer. With the technology that existed in the late 1980s, it was a nightmare version of "find the needle in the haystack" – with millions of potential needles in hundreds, and then thousands, of haystacks. But Isaacs, Ph.D., his dedicated research team and soon, collaborators at other institutions, plugged away. It made sense that a major mutation had to be out there: Something was clearly different with these families, most of whose men tended to develop prostate cancer, and at a younger age. But for a very long time, the genetic Holy Grail of a "highly penetrant" gene – a mutation that, if inherited, will dramatically raise a man's risk of developing prostate cancer – proved elusive.

Not anymore. In exciting work published in the New England Journal of Medicine early in 2012, Isaacs and colleagues at Johns Hopkins and the University of Michigan Health system reported finding what appears to be the first major gene mutation associated with a high risk of the disease in hereditary prostate cancer families. This research was made possible in large part through the generous support of Mr. P. Kevin Jaffe. Men who inherit this mutation are 10 to 20 times more likely to get prostate cancer than other men. (Hereditary prostate cancer was defined and characterized by Isaacs and Patrick Walsh in the late 1980s. About 25 percent of men with prostate cancer have a family history of the disease, but only about 3 or 4 percent of men have an inherited, genetic form that involves mutated genes, which can be passed on by either parent. Since then, Isaacs and colleagues had discovered several intriguing "prostate cancer genes," but no male equivalent of the BrCa1 and BrCa2 mutations in breast cancer.)

The gene in question is named HOX B13 and in its normal form, it's important in the development of the prostate before birth. When it is mutated, however, cell growth in the prostate is unchecked and cancer is a common result. In the study, multiple members of four different families – and every one of the men who developed prostate cancer – turned out to have this mutation. "This is what we have been looking for," says Isaacs, The William Thomas Gerrard, Mario Anthony Duhon and Jennifer and John Chalsty Professor of Urology, and The Dr. and Mrs. Peter S. Bing Scholar.

The scientists knew a major gene
mutation had to be there. More
than 20 years ago, they knew it.
They just couldn't find it.

His research has been generously supported by donors including Mr. P. Kevin Jaffe and the Peter Jay Sharp Foundation. "We have never seen anything like this before," adds Walsh, a co-author of the study. "It all came together to suggest that this single change may account for at least a portion of the hereditary form of prostate cancer." Among other implications, this discovery may lead to a genetic test that could help save lives as men who turn out to have this mutation begin regular screening, perhaps even starting as early as their thirties.

Together with colleagues at TGen in Arizona, the scientists studied genetic material from the youngest men diagnosed with prostate cancer in 94 families who had participated in studies at Johns Hopkins and the University of Michigan. Each family was hard hit by prostate cancer, with several close relatives (brothers, or fathers and sons) affected. Next, working with scientists at Wake Forest University, the researchers looked for the same mutation among 5,100 men who had been treated for prostate cancer at either Hopkins or the University of Michigan. The mutation was found in 72 of the men. These men also were much more likely to have at least one first-degree relative who also had been diagnosed with prostate cancer, and to have an early age at diagnosis.

This particular HOX B13 mutation was identified in families of European descent. Two other mutations on the same gene were also found in families of African descent; black men are more likely to be diagnosed with prostate cancer at a younger age, and to have aggressive cancer that needs curative treatment. "More research is needed before we understand the significance of these mutations," says Isaacs. "We need to continue studying HOX B13, and to expand our study to include larger groups of men." Isaacs also plans to develop a mouse model with this mutation (see story).

Until these results have been duplicated by other institutions and the risk for carriers to develop prostate cancer confirmed with more certainty, this test will not be available for general use.

Neither Isaacs nor Walsh believes the search for genes linked to hereditary prostate cancer is over. Far from it; in fact, "the complex genetic architecture of prostate cancer, with both common and rare mutated genes playing a role in inherited susceptibility, may help explain why it has taken so long to identify genes such as HOX B13," says Walsh. "It is likely that there are multiple, similar, rare but dangerous mutations that are responsible for hereditary prostate cancer, and that no one mutation will explain the majority of the cases. I believe we will find out that many roads lead to Rome."

Genes and Prostate Cancer:
26 Years of Genetic Discovery at the Brady


Patrick Walsh, who has been seeing increasingly younger men with prostate cancer, is struck by how many of them have a family history of the disease. One of his patients, a 49-year-old man, has an unforgettable legacy: Every male in his family has died of prostate cancer: His father, his father's three brothers, and his grandfather. Walsh, then Director of the Brady, launches the first of a series of genetic studies.



A study of 691 of Walsh's radical prostatectomy patients demonstrates that a family history of prostate cancer is a major factor that increases risk of the disease. Men who have a father or brother with the disease have a twofold higher risk, and this increases if there are three or more first-degree relatives affected.



Based on the data collected in Walsh's families, a study published in the Proceedings of the National Academy of Sciences demonstrates for the first time that the aggregation of cases in families is caused by Mendelian inheritance of a rare gene.

Based on the prior findings, the definition of hereditary prostate cancer (HPC) is developed, a definition that is used widely today: three or more first-degree relatives (father, son, brother), or three generations (grandfather, father, son), or two first-degree relatives if both are less than 55 years old. These are the families that are targeted for DNA analysis to search for specific mutations involved in the development of prostate cancer.

An estimated 17,000 fewer
men per year are diagnosed
with metastatic disease today,
compared to the pre-PSA era.

Using linkage analysis as a method to find genes causing prostate cancer (this has been compared to trying to find one misspelled word in 20 sets – each containing 20 volumes – of the Encyclopedia Britannica) Isaacs and colleagues report in Science magazine the first linkage between prostate cancer in families and a region of the genome located roughly in the middle on the long arm of chromosome 1. The scientists are optimistic that they will soon be successful in identifying genes like the BRCA1 and BRCA2 mutations in breast cancer. In 2002, they do identify mutations in two genes involved in inflammation, one on chromosome 1 (RNASEL, on the long arm of chromosome 1, a gene that codes for ribonuclease-L) and the other on chromosome 8 (MSR1, found on chromosome 8, which codes for macrophage scavenger receptor 1). But the effect of these genes on prostate cancer risk is small and variable from population to population. In all, Isaacs and colleagues toil for 16 years without success in finding a mutation that, if inherited, dramatically increases a man's risk of developing prostate cancer.


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