February 2012 eNewsletter
Researchers Find First Major Gene Mutation Associated with Hereditary Prostate Cancer Risk
A report on the discovery, published in the January 12, 2012 issue of the New England Journal of Medicine, was led by investigators at the University of Michigan 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 Kathleen A. Cooney, M.D., professor of internal medicine and urology at the U-M 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 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."
For this study, the researchers collaborated with John Carpten, Ph.D., at the Translational Genomics Research Institute (TGen) in Phoenix, Arizona, 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, Ph.D., 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.
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.
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 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 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," says Isaacs. He adds, "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. 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.
Cooney says patients with questions about prostate cancer screening, particularly if the disease runs in their families, are encouraged to speak with their doctor.
Story credit: Ian Demsky, UMHS PRMC
Miniature, Battery-Free Cardiac Implant Being Developed by Pediatric Researchers and Industry Partner
A miniature, battery-free, wireless, cardiac implant being developed by a U-M researcher and the Ann Arbor company Integrated Sensing Systems, Inc. (ISSYS), has received important funding that could get it to patients more quickly.
A $1.5 million grant from the National Institutes of Health (NIH), will help a research team, led by Martin Bocks, M.D., and ISSYS, to complete the final preclinical testing required before seeking approval under Food and Drug Administration's Humanitarian Device Exemption pathway. Bocks, a pediatric cardiologist with the University of Michigan Congenital Heart Center and Dr. Nader Najafi, CEO and President of ISSYS, are pictured above.
"We are extremely excited to continue working with ISSYS to develop a wireless, implantable pressure sensor for our patients with complex forms of congenital heart disease," says Bocks, the project's medical principal investigator.
"This pressure sensor has the potential to greatly improve the care we provide to our most complex patients and will provide us with unprecedented opportunities to learn more about their unique physiology. We appreciate the NIH and the National Heart Lung and Blood Institute (NHLBI) for their willingness to fund research on patients with rare, severe forms of congenital heart disease."
Bocks and his team at U-M have been working on this device -- which will be used in infants and children -- for three years. The 2.5-year grant will help test a device that will reduce the need for invasive cardiac catheterization procedures and provide a better understanding of congenital heart disease.
The device is a wireless, battery-free, miniature pressure sensor that is implanted within a heart chamber, Bocks says. Once implanted, doctors can measure pressure inside the heart while the patient is being seen in the outpatient clinic without having to do a heart catheterization. In the future, such monitoring may be performed remotely or from the home.
The device, which would stay in place permanently, is initially planned for use in patients with functional single ventricle conditions, such as hypoplastic left heart syndrome. It could be used in other forms of pediatric and adult heart disease in the future.
"We hope it would be going to market by year 2013," Bocks says. "We expect the device to decrease the number of heart catheterizations, help doctors better monitor the effects of medications, and provide early detection for conditions such as blood clots in lungs."
"We also hope that it will help us conduct more research," he adds. "We'll be able to obtain information from patients when they are sleeping, or exercising -- information we had not been able to get to before."
The device is important because it will allow researchers to conduct more tests on these patients, which will lead to better treatments, says Najafi.
"This grant helps us develop wireless, intelligent, miniature implants for patients with congenital and structural heart diseases. It paves the way for the start of clinical studies in infants and children with complex congenital heart defects," he says.
"The pediatric medical device field represents unique commercialization challenges due to its small size and stringent requirements," Najafi adds. "We are grateful to the NIH for this needed support for the challenging pediatric device field. The results of this effort will have important spillover effects for broader applications within the field of adult and pediatric cardiovascular medicine."
Story credit: Margarita Wagerson, UMHS PRMC
Combination of Oral Drugs Suppresses Common Type of Hepatitis C
A new combination of investigational drugs successfully suppressed hepatitis C genotype 1 infection in a high percent of patients who had not responded to previous treatment in a study led by a University of Michigan hepatologist.
The study, published Jan. 19 in the New England Journal of Medicine, focused on hepatitis C genotype 1, which is predominant in the United States and the most difficult to treat. Hepatitis C is a virus that infects the liver and can cause liver cancer and liver cirrhosis. It is transmitted through direct contact with infected blood and blood products.
In this pilot study, patients with hepatitis C genotype 1 infection, who had not responded to previous treatment with PEG-interferon alfa and ribavirin, were given a combination of two investigational direct-acting antiviral agents (daclatasvir and asunaprevir) alone, or were given these two antiviral agents along with PEG-interferon alfa-2a and ribavirin. All the patients saw their hepatitis C viral load drop rapidly, says Anna S. Lok, M.D., professor of Internal Medicine, Division of Gastroenterology at the University of Michigan Medical School and lead author of the study.
All 10 patients given the four drug treatment -- two direct-acting antiviral agents (daclastasvir and asunaprevir) that block the NS3 and NS5A regions of the hepatitis C virus plus PEG-interferon alfa and ribavirin -- had sustained virologic response with undetectable virus at the end of treatment and at 12 weeks after stopping treatment. Four of the 11 patients given the two direct-acting antiviral agents only also achieved sustained virologic response. A sustained virologic response or SVR means there is no detectable Hepatitis C virus in a patient's blood after treatment is stopped. Achieving sustained virologic response is important, because research has shown that late relapse is rare.
"The two recently approved hepatitis C drugs -- telaprevir or boceprevir -- combined with PEG-interferon alfa and ribavirin have limited success in patients who have not responded to previous treatment with PEG-interferon alfa and ribavirin. Because of this high unmet medical need, there is a necessity for new combination regimens that can increase response rates in that population," says Lok, who also is Director of Clinical Hepatology at U-M. "The high rate of sustained virologic response in patients who received the four drug regimen is very exciting. Although only four of 11 patients given the two direct-acting antiviral agents only achieved sustained virologic response, this is the first study to show that sustained virologic response can be achieved without the use of interferon or ribavirin. These data are very encouraging because PEG-interferon alfaand ribavirin are associated with many side effects and many patients with hepatitis C choose not to receive treatment for fear that they cannot tolerate those drugs."
An estimated 170 million people worldwide are infected with hepatitis C, with genotype 1 being the most prevalent genotype. Up to 80 percent of those infected with hepatitis C will become chronically infected. Twenty percent of people with chronic hepatitis C will develop cirrhosis and, of those, up to 25 percent may progress to liver cancer. Although there is no vaccine to prevent hepatitis C, it is a potentially curable disease.
In the Phase II clinical trial, Lok, along with a team of researchers including scientists from Bristol-Myers Squibb, studied patients with Hepatitis C genotype 1, who had not responded to prior therapy with PEG-interferon alfa and ribavirin. The study was funded by Bristol-Myers Squibb.
"Overall, these results suggest that further research into combinations of direct-acting antiviral agents, with or without PEG-interferon and ribavirin, should be encouraged," Lok says. "Caution must be exercised in selecting the right combination of direct-acting antiviral agents in studies of interferon-free regimens because in this study, all 7 patients who received only two direct-acting antiviral agents that did not achieve sustained virologic response had emergence of drug resistance variants to both drugs."
Story credit: Mary Masson, UMHS PRMC
