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 was published in the January 12, 2012 issue of the New England Journal of Medicine. UNC-Chapel Hill scientist Ethan Lange, PhD, was part of the team of investigators at the Johns Hopkins University School of Medicine, the University of Michigan Health System, Wake Forest University and the Translational Genomics Research Institute.
Lange is associate professor of genetics and biostatistics and a member of UNC Lineberger Comprehensive Cancer Center. The research team found that men with prostate cancer were 20 times more likely to carry this mutation than screened men without prostate cancer.
Lange explains, "For the first time we have identified an inherited high-risk mutation for prostate cancer. The mutation is significantly more common in men with a family history of prostate cancer that strikes at an earlier age, compared to older patients with no family history. Our findings suggest it could be a valuable early screening tool for men, particularly those with a family history of early-onset disease. The benefit to this population of men could be similar to the benefit of current screening strategies employed for BRCA1 and BRCA2 mutations in women with family history of early-onset breast cancer.
"There is still work to be done regarding understanding the biological function of the mutation and the precise level of absolute risk for carriers of this mutation -- a process that took years for the BRCA1 and BRCA2 genes. Still, our results strongly suggest this is the most clinically important mutation identified for prostate cancer to date."
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.
James P. Evans, MD, PhD, Bryson Distinguished Professor of Genetics in the UNC School of Medicine, leads UNC Lineberger's clinical genetics program and is an internationally recognized expert in clinical cancer genetics. He was not involved in the study, but observes, "The genetics of prostate cancer have proven surprisingly difficult to unravel and this work represents significant and welcome progress. While fewer than one percent of Caucasian men carry the described mutation in this particular gene, for those men who do carry it, the increased risk for developing prostate cancer is likely greater than for any previous mutation found to date. Larger follow-up studies will be necessary to understand the importance of this finding for prostate cancer, and it remains to be seen whether this mutation is associated with other cancers."
Lange and Kathleen Cooney, MD, one of two study senior authors, were the first to identify the human chromosome region of interest where the mutation, called HOXB13, was ultimately found. Lange, who has been a collaborator on Dr. Cooney's University of Michigan Prostate Cancer Genetics Project for 17 years, led the statistical analyses and was actively involved in designing the study and interpreting the findings for the current study.
This particular mutation was found in families of European descent, while two different mutations on the HOXB13 gene were identified in families of African descent. Since only seven of the 94 families studied were of African descent, more research will be required before the significance of those mutations is known. African-American men are more likely to be diagnosed with prostate cancer at younger ages and have a more aggressive form of the disease.
Lange concludes, "Over the past couple years, genetic sequence analysis -- the ability to evaluate nearly every base of the DNA code over large genomic regions as opposed to a relatively small number of preselected bases -- has become possible for large research studies. The National Institutes of Health and private research companies have invested hundreds of millions of dollars into developing this technology, and our results represent one of the first successes demonstrating its use in identifying a strong but uncommon genetic risk factor for a common disease. This new technology should, in the near future, lead to many exciting discoveries of genes important to a wide range of common, complex human diseases."
Other UNC authors are: Yunfei Wang, MS, a statistician in the department of genetics, and Chris Bizon, PhD, a senior research scientist with UNC's Renaissance Computing Institute.
- Charles M. Ewing, Anna M. Ray, Ethan M. Lange, Kimberly A. Zuhlke, Christiane M. Robbins, Waibhav D. Tembe, Kathleen E. Wiley, Sarah D. Isaacs, Dorhyun Johng, Yunfei Wang, Chris Bizon, Guifang Yan, Marta Gielzak, Alan W. Partin, Vijayalakshmi Shanmugam, Tyler Izatt, Shripad Sinari, David W. Craig, S. Lilly Zheng, Patrick C. Walsh, James E. Montie, Jianfeng Xu, John D. Carpten, William B. Isaacs, Kathleen A. Cooney. Germline Mutations inHOXB13and Prostate-Cancer Risk. New England Journal of Medicine, 2012; 366 (2): 141 DOI: 10.1056/NEJMoa1110000
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