Discovery
January 01, 2017

“Family history is a powerful tool, but we need to better characterize what kind of family history is most meaningful.”

If you have breast, colon, ovarian, or pancreatic cancer in your family, you may be at risk for the most aggressive kind of prostate cancer. This is important news, because for years scientists didn’t make the connection between prostate cancer and other cancers that run in families.

But now, thanks to new work by William Isaacs, Ph.D., The William Thomas Gerrard, Mario Anthony Duhon, Jennifer and John Chalsty Professor in Urology, and colleagues, and several other research groups around the world, we know that there is a short list, a genetic “who’s who” of very bad genes that appear in lethal prostate cancers; these mutated genes are also involved in the worst cancers of the breast, colon, ovaries, and pancreas. They can be inherited by men and women.

The job description for these genes is “DNA damage repair,” and normally, they are supposed to protect the body against the very genetic mistakes that can lead to cancer. Imagine a car factory where someone in charge of quality control breaks his eyeglasses: He misses delicate mistakes in the machinery he’s supposed to inspect; those faulty parts then get put into bigger sections, and before you know it, a defective engine is on its way out the door.

If you have slow-growing prostate cancer, chances are that you do not have one of these damaged genes. In fact, “in many studies of men with less aggressive disease, we have been unable to detect genes linked to lethal prostate cancer,” Isaacs says. He should know; he has identified many genetic variants called SNPs that raise a man’s risk of getting prostate cancer. But these bad stretches of DNA just raise the risk by a very small amount, and just because a man inherits one of them doesn’t necessarily mean that he will get prostate cancer, or that it will be the aggressive kind that really needs to be treated.

In the first study of its kind, Isaacs and colleagues including Jianfeng Xu at NorthShore Research Institute in Chicago recently completed a detailed genetic analysis of 96 men who died of prostate cancer at an early age – younger than 65. “We sequenced all regions on each chromosome that code for proteins,” Isaacs explains. “Surprisingly, we found that more than 20 percent of these patients carry inherited mutations which inactivate a class of genes responsible for repairing damaged DNA.” This is a huge percentage. “This compares to a rate of around 3 percent in men selected for positive family history only. Other recent studies by Stand up to Cancer investigators are finding similar results.”

Two of these genetic culprits are BRCA1 and BRCA2; as genes go, they are most famous for their role in inherited breast and ovarian cancer. Others are ATM, PALB2, PMS2, and MSH2, “which typically are associated with breast, pancreatic and colon cancer. “We found the highest frequency of mutations in BRCA2,” says Isaacs. “Studies are under way worldwide to more fully characterize the role of this heretofore breast cancer gene in inherited prostate cancer. Family history is a powerful tool, but we need to better characterize what kind of family history is most meaningful. While much work remains to be done to fully understand these results, we are very excited about these new findings and how they may translate into better ways to identify a man’s risk for aggressive prostate cancer before the cancer even begins.”