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- Posted Wednesday January 11, 2012
TGen and its collaborators find first major gene mutation associated with hereditary prostate cancer risk
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.
# # #
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
