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A RARE MUTATION THAT INCREASE PROSTATE CANCER RISK

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Researchers have discovered a "rare but recurrent" genetic mutation that is associated with a significantly higher risk for hereditary prostate cancer.
A report on the finding appears in the January 12 issue of The New England Journal of Medicine.
The discovery has no immediate impact on clinical practice because a commercial test is not available.
"Our findings need to be reproduced in additional populations before...there are sufficient data to support developing a clinical test," Kathleen Cooney, MD, one of the study's senior authors, toldMedscape Medical News. She is professor of internal medicine and urology at the University of Michigan Medical School in Ann Arbor.
Still, the discovery is big news. "This is the first major genetic variant associated with inherited prostate cancer," said Dr. Cooney in a press statement.
Prostate cancer has long been identified as having a "strong familial component," but identifying a genetic basis for the phenomenon has been elusive in the past, write Dr. Cooney and her coauthors in their paper.
In their preliminary work, the investigators found that in 4 selected families with a pronounced history of prostate cancer, all 18 males with the disease had a G84E mutation in the HOXB13 gene, which is important in prostate development.
This HOXB13 G84E mutation, now also identified as rs138213197, is novel; it has not been reported elsewhere in major gene sequencing databases.
Dr. Cooney and colleagues looked for the newly documented mutation in 5083 white men who had prostate cancer (but who were unrelated to each other) and in 1401 control subjects without prostate cancer.
They found the mutation in 72 men (1.4%) with and in 1 man without (0.1%) prostate cancer. Thus, the carrier rate was 20 times higher in men with than in men without prostate cancer.
The investigators analyzed these 5083 men with prostate cancer by age at disease onset and by the presence of any history of prostate cancer in their families. The mutation was significantly more common in men with early-onset familial prostate cancer (3.1%) than in those with late-onset nonfamilial prostate cancer (0.6%) (P = 2.0 × 10−6).
The HOXB13 G84E mutation is rare, the authors point out; it apparently occurs in only 1.4% of all men with prostate cancer. However, the relative rarity of the mutation has not dampened the spirits of the investigators.
"It's what we've been looking for over the past 20 years," said William B. Isaacs, PhD, the study's other senior author. He is professor of urology and oncology at the Johns Hopkins University School of Medicine in Baltimore, Maryland. "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."
The investigators hope that other groups will attempt to validate their findings. Dr. Cooney and her team are already doing further studies. But a test for the genetic mutation will have to overcome some hurdles, she explained.
"If our findings hold up, it may be possible to offer testing to unaffected men within a family in which the proband [the first member identified with prostate cancer] carries a HOXB13 mutation," she said.
But this is currently "premature," given the unknowns at the moment. "Because we do not know the penetrance of any of the HOXB13 mutations, we would not be able to offer clinical advice to men found to be mutation carriers. In other words, we would not be able to tell them the likelihood of being diagnosed with prostate cancer in their lifetime or if PSA testing would be useful," she said.
Other Rare Variants Could Be Found
This study might lead to more discoveries of the genetic causes of inherited prostate cancer, say the authors.
"This work suggests that future DNA sequencing studies using next-generation technology and study populations enriched for genetic influence (as evidenced by an early age at onset and positive family history) may identify additional rare variants that will contribute to familial clustering of prostate cancer," they write.
This "next-generation technology" was pivotal to the discovery of the HOXB13 G84E mutation.
Improved gene sequencing technologies allow for more "rapid and comprehensive" investigation of genomics, the authors say. In this case, the researchers sequenced the DNA of more than 200 genes in a human chromosome region known as 17q21–22. This has been "one of the most intensely investigated regions of the genome for prostate cancer susceptibility," they point out.
The study received funding support from William Gerrard, Mario Duhon, John and Jennifer Chalsty, P. Kevin Jaffe, and the Patrick C. Walsh Prostate Cancer research fund. The Department of Network and Computing Systems at TGen, with support from National Institutes of Health grants, facilitated the use of supercomputing resources.

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