After a 20-year quest to find a genetic driver for prostate cancer that strikes men at younger ages and runs in families, researchers have identified a rare, inherited mutation linked to a significantly higher risk of the disease.
A report on the discovery, published in the Jan. 12 issue of the New England Journal of Medicine, was led by investigators at the U-M Health System and Johns Hopkins University School of Medicine. The research team found that men who inherit this mutation have a 10 to 20 times higher risk of developing prostate cancer.
While accounting for only a small fraction of all prostate cancer cases, the discovery may provide important clues about how this common cancer develops and help to identify a subset of men who might benefit from additional or earlier screening. This year, an estimated 240,000 men in the United States will be diagnosed with prostate cancer.
“This is the first major genetic variant associated with inherited prostate cancer,” says Dr. Kathleen Cooney, professor of internal medicine and urology at the Medical School, one of the study’s two senior authors.
“It’s what we’ve been looking for over the past 20 years,” adds William Isaacs, professor of urology and oncology at the Johns Hopkins University School of Medicine, the study’s other senior author. “It’s long been clear that prostate cancer can run in families, but pinpointing the underlying genetic basis has been challenging and previous studies have provided inconsistent results.”
For this study, the researchers collaborated with John Carpten, Ph.D., at the Translational Genomics Research Institute (TGen) in Phoenix, Ariz., who used the latest technology to sequence the DNA of more than 200 genes in a human chromosome region known as 17q21-22. Cooney, working with Ethan Lange, of the University of North Carolina on the U-M Prostate Cancer Genetics Project, was the first to identify 17q21-22 as a region of interest.
“We found that the mutation was significantly more common in men with a family history and early diagnosis compared with men diagnosed later, after age 55, without a family history. The difference was 3.1 percent versus 0.62 percent,” Cooney says.
The researchers say with further study, it may be possible one day to have genetic test for inherited prostate cancer in much the same way that tests are available to look for BRCA1 and BRCA2 mutations that greatly increase a woman’s chance of developing breast and/or ovarian cancer.
“We need to continue studying this variant and look at larger groups of men. Our next step will be to develop a mouse model with this mutation to see if it causes prostate cancer,” Isaacs says. He adds, “Future DNA sequencing may also identify additional rare variants that contribute to prostate cancer risk in families.”
Cooney says patients with questions about prostate cancer screening, particularly if the disease runs in their families, are encouraged to speak with their doctor.
Additional U-M authors are Anna Ray, Kimberly Zuhlke and Dr. James Montie.
