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Discovery published in New England Journal of Medicine may provide clues about disease development and risks

PHOENIX, Ariz. - Jan. 11, 2012 - Researchers at the Translational Genomics Research Institute (TGen) and its collaborators have identified a rare, inherited mutation linked to a significantly higher risk of prostate cancer.

A study led by Johns Hopkins University School of Medicine and the University of Michigan Health System published today in the New England Journal of Medicine follows a 20-year quest to find a genetic driver for an aggressive type of prostate cancer that strikes men at younger ages and runs in families. Researchers found that men who inherit this mutation have a 10-20 fold higher risk of developing prostate cancer.

"The results of this study represent an amazing advancement in our understanding of inherited prostate cancer. It is our hope that this information will provide new opportunities for diagnosis, prevention, and treatment of prostate cancer in patients with a strong family history of the disease," said Dr. John Carpten, Ph.D., Director of TGen's Integrated Cancer Genomics Division and a co-investigator on the study.

Led by Dr. Carpten, TGen sequenced the DNA of more than 200 genes on a human chromosome region known as 17q21-22.

Dr. Kathleen A. Cooney, M.D., professor of internal medicine and urology at the U-M Medical School, and one of the study's two senior authors, worked with Dr. Ethan Lange, Ph.D., of the University of North Carolina on the U-M Prostate Cancer Genetics Project and were the first to identify 17q21-22 as a region of interest.

While accounting for only a small fraction of all prostate cancer cases, the most recent 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 U.S. will be diagnosed with prostate cancer.

"This is the first major genetic variant associated with inherited prostate cancer," Cooney said.

"It's what we've been looking for over the past 20 years," adds Dr. William B. Isaacs, Ph.D., 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."

Researchers started with samples from the youngest patients with prostate cancer in 94 families who had participated in studies at U-M and Johns Hopkins. Each of those families had multiple cases of the disease among close relatives, such as between fathers and sons or among brothers.

Members of four different families were found to have the same mutation in the HOXB13 gene, which plays an important role in the development of the prostate during the fetal stage and its function later in life. The mutation was carried by all 18 men with prostate cancer in these four families - which was all the men with the disease from whom DNA was available.

The researchers collaborated with Jianfeng Xu, Ph.D., and Lilly Zheng, Ph.D., at Wake Forest University to look for the same HOXB13 gene mutation among 5,100 men who had been treated for prostate cancer at either Johns Hopkins or U-M. The mutation was found in 1.4 percent, or 72, of the men. It turned out that those men were much more likely to have at least one first-degree relative, a father or brother, who also had been diagnosed. The researchers also looked for the mutation in a control group of 1,400 men without prostate cancer, and only one of those men carried the mutation. In addition, the researchers studied men who were specifically enrolled in studies of early-onset or familial prostate cancer.

"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.

"We had never seen anything like this before. It all came together to suggest that this single change may account for at least a portion of the hereditary form of the disease," says study co-author Dr. Patrick Walsh, M.D., professor of urology at Johns Hopkins, who is one of the pioneers in prostate cancer treatment. In the 1980s, Walsh was one of the first to publish a study showing that the risk of prostate cancer was higher among men with close relatives who also had the disease.

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 BRCA 2 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. "Future DNA sequencing may also identify additional rare variants that contribute to prostate cancer risk in families."

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. African American men are more likely to be diagnosed with prostate cancer at younger ages and have a more aggressive form of the disease.

Cooney says patients with questions about prostate cancer screening, particularly if the disease runs in their families, are encouraged to speak with their doctor.



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Additional authors:

Anna M. Ray, M.S., Kimberly A. Zuhlke, B.A., James E. Montie, M.D., of U-M
Charles M. Ewing, M.S., Kathleen E. Wiley, M.S., Sarah D. Isaacs, M.S., Dorhyun Johng, B.A., Guifang Yan, B.S., Marta Gielzak, B.A., Alan W. Partin, M.D., Ph.D., of Johns Hopkins.
Yunfei Wang, M.S., of the University of North Carolina.
Chris Bizon, Ph.D., of Renaissance Computing Institute, Chapel Hill, N.C.
Christiane M. Robbins, M.S., Waibhav D. Tembe, Ph.D., Vijayalakshmi Shanmugam, Ph.D., Tyler Izatt, M.S., Shripad Sinari, M.S., David W. Craig, Ph.D., of Translational Genomics Research Institute (TGen).

Funding and acknowledgements: William Gerrard, Mario Duhon, John and Jennifer Chalsty, P. Kevin Jaffe and Patrick C. Walsh Cancer research fund. The authors also thank the Lung GO Sequencing Project, WHI Sequencing Project, Broad GO Sequencing Project, Seattle GO Sequencing Project and Heart GO Sequencing Project. The Network and Computing Systems department of TGen, with support from National Institutes of Health grants, facilitated the use of supercomputing resources.

Citation: "Germline Mutations in HOXB13 and Prostate Cancer Risk," New England Journal of Medicine, TK-DATE.

For more about this study, see the Johns Hopkins news release at: http://www.hopkinsmedicine.org/news/media/releases


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