Discovery Winter 2019
November 2, 2018

"How many more BRCA2-like genes can predict aggressive disease risk and drug sensitivity? So far, the list of these genes is quite short."

“Every year, worldwide, an estimated 1,111,700 men are diagnosed with prostate cancer and 307,500 men die from it,” says William Isaacs, Ph.D., the William Thomas Gerrard, Mario Anthony Duhon and Jennifer and John Chalsty Professor of Urology. “The wide discrepancy between these two numbers shows that only a subset of these cancers progress to lethal disease.” This is good news for most men with prostate cancer – but men who have, or are at risk of getting, aggressive prostate cancer are desperately in need of smarter diagnosis and more specific treatment.

The key to more precise treatment for aggressive prostate cancer is in understanding the genes of that man’s specific cancer. Some drugs work much more effectively against particular mutated genes when cancer has escaped the prostate. Even when cancer is caught in the early stages, it’s critical to understand a man’s genetic risk – whether his cancer is aggressive or more benign.

A mutated version of the HOXB13 gene, discovered by Isaacs and his team, is the first verified prostate cancer susceptibility gene. Isaacs and colleagues at other centers have also discovered that more commonly mutated genes – defects that can cause several different types of cancer – are major factors in inherited prostate cancer risk, as well. For example, “work from our lab and others has shown that BRCA2 mutations increase the risk not only for prostate cancer, but for an aggressive form,” says Isaacs. In fact, “we now know that about one in 10 men who die from prostate cancer carry a damaged copy of BRCA2 or another gene involved in DNA repair, such as ATM.”

Finding one of these mutations in a man with prostate cancer has implications for his family, as well: “each child has a one-out-of-two chance of inheriting the risky gene. How many more BRCA2-like genes can predict aggressive disease risk and drug sensitivity?” Isaacs wonders. “So far, the list of these genes is quite short.”

As part of The Patrick C. Walsh Hereditary Prostate Cancer Program, “in an effort to find additional genes that can predict prostate cancer risk, we have begun a large study, sequencing each of the over 20,000 inherited genes from different sets of prostate cancer patients: men with highly aggressive or lethal disease, men with more indolent or benign disease, and men with multiple affected family members.”

So far, Isaacs and his team have found a number of candidate susceptibility genes: mutated genes that are more common in men with aggressive disease than in men with low-risk disease, and are present in multiple members of prostate cancer families. “We are in the process of testing these candidates now,” says Isaacs. “So far, at least one gene has emerged that is worthy of further study: a gene called PPFIBP2, which also has been implicated in metastatic breast cancer. “They have found mutations in this gene more often in men with aggressive prostate cancer than in men either with less-aggressive disease, or men who don’t have prostate cancer. Also,“we have observed multiple families where each affected member carries the same mutation in this gene.”

Much more work is needed, Isaacs notes. One day, he hopes, the presence or absence of such genes “will guide our treatment decisions, so that every man is treated appropriately for his specific prostate cancer risk.”