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Posts Tagged ‘Ohio State University’


Reporter: Aviva Lev-Ari, PhD, RN

Educating Physicians on Genomic Medicine

October 2012

Medical schools across the US are busy this fall, preparing students for the impending transformation in healthcare that advances in genomic knowledge promise to bring.

After only eight weeks of medical coursework, students at Ohio State University will be thrown into a real-world learning environment where they will use patients’ genomic and behavioral risk factors to encourage healthier lifestyles. Medical and PhD students at Stanford University, meantime, have the opportunity to get their own DNA tested and learn how genes influence disease risk and drug response in the context of their own health. And at the University of Florida, medical and pharmacy students will soon be able to practice clinical interactions with digital avatars that can mimic patients with various genetic conditions.

Medical schools are developing such innovative curricula as it becomes increasingly clear that physicians are ill-equipped to practice genomically guided personalized medicine — a discipline that requires doctors to consider a patient’s genomic data in the context of other medical and family history and craft a unique treatment plan. A survey of 800 physicians from last year revealed that, although the majority of respondents believes personalized medicine will influence how they care for patients in coming years, only 10 percent of primary care doctors and cardiologists and 30 percent of oncologists feel they are up to speed with the latest advances in the field.

The same survey, conducted by healthcare communications firm CAHG, found that only 20 percent of practicing physicians had received any training on how to administer genomically guided medicine. The outlook improves somewhat for more recently minted doctors, with around 50 percent of those who graduated from medical school in the past five years reporting that they have had some form of training in personalized medicine.

The challenge of keeping doctors up to date on the latest medical advances looms particularly large considering that, by 2021, spending on genetic testing is projected to jump to $25 billion from $5 billion currently. However, physicians’ limited genomics know-how isn’t the only barrier to the adoption of personalized medicine into mainstream care. While many healthcare providers are enthusiastic about using genomic tools to improve their patients’ health, there are a number of systemic challenges — slow turnaround times for test results, insurers’ reluctance to pay for new technologies, and the lack of genomic data in electronic medical records — that keep them from effectively using these tests.

“Personalized medicine is an ecosystem or a value chain,” says Larry Lesko, who left the US Food and Drug Administration last year to head Florida’s new Center for Pharmacometrics and Systems Pharmacology. “In this ecosystem … there is a lot more than physician education.”

Even if medical students leave academia with knowledge of genomic medicine, in the short term very few will get to apply those principles at a community practice or a hospital. “Unless what we’re teaching them is what they see in the clinical environment, wherever they go from here [they will face] substantial barriers,” says Daniel Clinchot, associate dean for medical education at Ohio State’s medical school. “[Unless] we can ensure that, across the US, we are holding physicians accountable for using the most up-to-date information and the way that information is applied, that sort of undoes the … medical education they received.”

Simulated reality

Physicians today have plenty of reasons not to practice genomic medicine. Take the anticoagulant warfarin for example. Although there is evidence that with genetic testing doctors can dose the drug more accurately than with standard methods and avoid hospitalizations due to adverse reactions, most doctors don’t use it because turnaround times for test results are too long to be useful for patients with acute conditions. For the majority of genetic tests, however, doctors find limited evidence backing their validity and utility in improving patients’ health. Even for genetic tests that are well validated, physicians are wary of coverage denials from insurance companies because there is little proof that the test is cost-effective compared to standard interventions. Meanwhile, healthcare providers who are eager to implement genetic testing more broadly in their practices find it difficult to do so with the dearth of genetic counselors and within the average eight-minute physician-patient interaction.

When developing genomic medicine courses, universities are keeping these realities in mind. With Lesko’s leadership, Florida is testing out the theory that physicians will be more likely to use genomic data in patient care if the information is readily available in electronic medical records.

Patients treated at Florida’s catheterization lab will receive a multi-gene test that doctors will use to discern whether the patients are likely to be poor responders to the antiplatelet drug Plavix and are at heightened risk for cardiac events. If, at a later time, a physician prescribes Plavix to a patient deemed to be a poor responder by genetic testing, the doctor will receive a “best practices advisory alert” in the patient’s EMR, recommending a different treatment strategy.

For the time being, only the test results related to Plavix response are included in the EMR. With patient consent, data on 249 other gene variations the test gauges will be stored in a secure database for research use.

Through this effort, doctors will learn how to consider genomic data in the context of a patient’s overall medical history, but they won’t have to worry about some of the procedural headaches, such as lengthy turnaround times for results, that deter the adoption of many tests by primary care physicians. “You have to focus on education of physicians at the right time,” Lesko says. “If you do it too early, when the infrastructure in somebody’s practice isn’t set up, I don’t think physicians will care, and they won’t retain the knowledge. But if you have the test results already available in the EMR, like we’re doing, then that’s the right time to do the training.”

Similarly, Florida plans to teach its medical students how to discuss genomic information with patients, with the help of digital simulations. Lesko envisions that medical and pharmacy students will be “able to practice clinical care” by interacting with avatars that can “realistically imitate patients with different genetic [data].”

For a few hundred dollars, consumers increasingly have access to genetic testing for numerous health conditions from companies such as 23andMe and Decode Genetics. A doctor with limited genomic knowledge could be at a loss for what to do with a patient who brings in a report with a slew of genetic test results. Under the Florida program, students would learn how to discuss genetic test results with an avatar that behaves like a patient with such a report.

“The idea is to get medical and pharmacy students involved in an active learning process,” Lesko says. “Retention of information [through such simulation programs] is usually fairly high.”

At Ohio State, meanwhile, the focus is on teaching medical students not just how to treat patients, but how to inspire them to stay healthy. “The students learn to be health coaches, which is extremely important in the transformation of medicine,” says Ohio State’s Clinchot. Genomics, particularly in the context of oncology, as well as the principles of P4 medicine — short for predictive, preventive, personalized, and participatory medicine — will be a big part of the students’ four-year training.

“We really try to focus on healthy behaviors by teaching students that they not only need to care for patients with disease, but also care for patients who are healthy currently, but have risk factors for certain things — whether they are genetic or behavioral — so they can [learn] how to prevent the development of things like type 2 diabetes,” Clinchot says.

In creating this program, Ohio State ran a pilot effort where students helped type 2 diabetes patients make lifestyle changes. The project showed that the students’ efforts resulted in patients adhering better to their medication regimens and feeling more in control of their diabetes. This pilot didn’t gauge the impact of DNA information on patient behavior, but Clinchot says that when genetic risk data is conveyed in the context of a more in-depth patient-physician interaction, the effect will be similarly positive.

Previous studies, such as one from the Multiplex Initiative by the National Human Genome Research Institute and a behavioral project conducted by the Scripps Translational Research Institute, have reported that genetic data has a limited impact on people’s behavior and that a minority of people share their test reports with genetic counselors or doctors. However, these surveys also found those who shared their test results with their doctors were the most motivated to make lifestyle changes.

“It’s not enough that you tell a patient [their genetic test results], sort of go over their risk factors and let them go and that’s it,” Clinchot says. “It’s [with] long-term follow up and the coaching aspect of it … that you’ll see a big difference.”

Real world data

Back in the real world, insurers get a little nervous every time a university starts implementing forward-thinking genomic testing programs, such as UF’s multiplex testing effort. They fear that if more people find out about these academic programs, it will raise consumer expectations that these tests — most of which insurers currently consider investigational and not ready for broad implementation — will soon be available at community practices and hospitals.

At the 2010 ECRI Institute’s annual conference, which brought together insurers and academics involved in personalized medicine, Barry Straube, then chief medical officer of the Centers for Medicare & Medicaid Services, expressed concern over efforts at Brigham and Women’s Hospital in Boston to conduct genetic testing to personalize cancer treatment and include this data alongside patients’ medical information in an electronic database for research.

“The reality, although all this is very important and absolutely essential to clinical research, is that when the rubber hits the road, and patients … start coming into medical offices and requesting access to various genetic tests and treatments … the enormity of the cost to society is frightening,” Straube said at the time.

It is no surprise, then, that outside of academia, insurance hurdles seem to be the biggest headache for community physicians administering genetic testing. “Over the last few years genetic testing has become more available, but some of the insurance companies haven’t really acquiesced [with coverage], which has been a real problem with providing testing to families with genetic disorders,” says Michael Mirro, a cardiologist and the medical director of the research center at Parkview Health, a non-profit health services provider in northeast Indiana.

“Medical students may be getting more genomics education, but they’re going to be really frustrated when they start practicing,” Mirro adds.

As an example, Mirro had to work for years, appealing a string of coverage denials, to convince insurer Anthem Blue Cross Blue Shield to pay for a $500 genetic test to see if a patient’s seven children had inherited the heart condition hypertrophic cardiomyopathy — the most common cause of sudden cardiac death in athletes and individuals 35 years old and younger. Since the patient, 38-year-old Matt Christman, carries a gene mutation for hereditary HCM, there is a 50 percent chance that his children are also carriers of this mutation. Mirro thought that testing Christman’s children for the mutations would be a better option than the alternatives — a $1,000 annual heart ultrasound or even pricier imaging tests — and would allow the family to more closely monitor the at-risk children carrying the HCM-associated gene mutation.

After patient groups started lobbying on behalf of Christman’s children and their story was recounted in the media, WellPoint’s Anthem Blue Cross Blue Shield unit agreed to pay for genetic testing for three of the oldest children. However, this was an exception, and the insurer’s latest coverage policy for genetic testing for HCM still deems the intervention “investigational and not medically necessary.” While the American Heart Association and the American College of Cardiology recommend genetic testing of HCM patients’ close relatives, Anthem has said it will require evidence from larger, more rigorously conducted studies that show genetic testing is useful in determining whether someone is at risk for the disease.

“Only with extreme lobbying and pressure are most genetic tests covered,” Mirro says. “Right now, it’s one battle at a time. … Even if physicians know the value of a genetic test most won’t order it because coverage of genetic tests requires an incredible sequence of bureaucratic events that chews up not only their time, but their staff’s time, which costs money.”

Mirro’s difficulties getting coverage for HCM genetic testing for the Christman children didn’t deter him, though, from providing genetic testing services at Parkview Research Center. If anything, it was a learning experience that inspired him to make changes at the research facility. He recently hired a genetic counselor to educate patients about diseases and discuss what test results might mean for their health and families.

Additionally, the research unit is in the process of setting up genetic testing to gauge whether patients who have recently undergone a stent procedure harbor mutations that make them more likely to be poor responders to Plavix. Mirro and his colleagues will follow patients who received this testing and collect data on whether the intervention helped avoid costs due to adverse events and if treating patients with other anti-platelet drugs improved their health.

Having learned that the only way to broadly affect payor policies on genetic tests is with evidence of their usefulness and cost effectiveness, Mirro says he has gotten “very involved with trying to look at the clinical outcomes of patients who have undergone testing and their families to see if there is value in providing these tests.”

With insurers’ increasing data demands for genetic tests, universities are also taking on this kind of research. On the one hand, by setting up a genetic testing program for Plavix and inputting the results into EMRs, the University of Florida is enabling academic physicians to practice personalized medicine. On the other hand, the project is also testing the hypothesis that analyzing many gene variations at once — and before certain conditions manifest in patients — is a cheaper and more efficient way to implement genomic testing in mainstream care.

As the cost of developing genomic tools decreases, the diagnostics industry is moving toward multiplex tests that analyze tens or hundreds of genes at once. However, unwilling to pay for the analysis of gene markers that have the potential to affect future healthcare decisions — but have no immediate impact on treatment — insurance firms currently pay for very few genetic tests that gauge multiple genes linked to a variety of conditions.

If the data collected as part of the Florida project show that multiplex testing is cost-effective, that may convince some payors to cover it. The program is “really a test of the information and the theory that having genetic testing information preemptively is good, having the data in the EMR is a good place to put it, and having it ready at the bedside is a way to facilitate adoption,” Lesko says.

Learning moments

For emerging technologies competing for adoption with established standards of care, industry is often in the best position to not only educate end users, but also lower many of the hurdles hindering uptake. As one of the first companies to commercialize gene expression profiling for breast cancer recurrence, molecular diagnostics company Genomic Health has found physician education to be a critical component of its success.

In 2004, when Genomic Health began marketing Oncotype DX — a test that assesses whether a patient’s disease will return and if she would benefit from chemotherapy — oncologists were used to tracking disease progression by examining the features of a tumor under a microscope, and genomic medicine wasn’t on medical schools’ radar screens. So it was up to the company to address the barriers keeping doctors from using its test, including convincing doctors of its value, making it easier for doctors to provide testing, and getting insurers to cover the diagnostic, which costs several thousand dollars.

Over the years, the company has focused not just on increasing the number of doctors who use Oncotype DX, but on teaching them how to use the test in the proper clinical scenario. For example, clinical validation studies for Oncotype DX have shown that the test determines recurrence risk and chemotherapy benefit only in patients whose tumors are driven by estrogen — a fact the company prominently highlights in brochures, in patient reports, through its sales teams, and in scientific publications. However, in the early days when Oncotype DX was a new test for oncologists, for every tumor sample submitted for testing, Genomic Health’s lab technicians looked at the estrogen receptor level in the tumor sample, and, if it seemed more typical for an ER-negative tumor, the company called the doctor to double-check the ER status of the tumor and reemphasize that Oncotype DX is only for ER-positive disease.

“We knew that one of our obligations was to inform physicians who were ordering the test that they should only test tumors that are ER positive,” says Genomic Health Chief Medical Officer Steve Shak. “We did catch some ER-negative samples that way and cancelled the tests. It was a tremendous educational moment for us and for the physicians.”

Moreover, Genomic Health has published studies involving more than 4,000 patient samples showing that by using the Oncotype DX risk score, in addition to traditional risk factors, physicians can better assess which women are at high or low risk of breast cancer recurrence. Those women Oncotype DX deems to be at low risk of recurrence can be treated with hormonal treatment, avoiding the adverse reactions and costs of chemotherapy.

The strength of the available evidence on Oncotype DX has had the most influence on physician adoption of the test and on insurance companies’ coverage policies, the company says. Genomic Health recently reported data from a Canadian study showing that after receiving Oncotype DX results, physicians changed their decision to give patients chemotherapy for 30 percent of women with early stage, localized breast cancer. In the US, 98 percent of women with breast cancer that hasn’t spread to the lymph nodes have coverage from private payors for Oncotype DX. Medicare also pays for the test.

Meanwhile, Genomic Health’s team of 120 so-called regional oncologic liaisons help physicians figure out the logistical issues that might keep them from using the test, such as how to order the diagnostic, what types of samples they need to submit, and how long it will take to get the results back. Genomic Health also operates a customer service call center that fields an average of 10,000 calls per month.

“This is the type of investment in physician education it takes to be a successful molecular diagnostics company,” Shak says. Genomic Health, which reported more than $200 million in revenues last year, wouldn’t disclose how much it spends on physician education efforts for Oncotype DX. The company, though did report spending about $84 million on sales and marketing efforts in 2011. To date Genomic Health’s strategy has swayed 10,000 physicians to order the test for more than 300,000 patients.

While, industry marketing might drive physician adoption, too aggressive marketing that doesn’t conform to treatment guidelines may raise red flags among insurers. Myriad Genetics’ BRACAnalysis dominates the BRCA1/2 mutation testing market for hereditary breast and ovarian cancer, but insurers have said that 20 percent or more of those tests are being performed for women who don’t meet testing guidelines.

Further, industry-driven education efforts are usually centered around specific products and target a particular physician specialty. These piecemeal programs don’t address the overwhelming need to educate doctors across disciplines and in an independent forum about genomic medicine. Cardiologist Eric Topol has said that he wants to develop a free online certification course on genomic medicine for all physicians, but the effort has been hindered by limited funding and the fragmented nature of medical practice today.

According to Topol, chief academic officer of Scripps Health, there isn’t one group or venue where such a broadly targeted genomics course can be housed. WebMD reaches only half of the 700,000 doctors in the US, while the American Medical Association has around 200,000 members.

“If we just set up a website and say, ‘Come to us,’ that’s not going to work,” he says. Introducing the course by specialty would take too long and cost even more, Topol adds. Although organizers of the program, called the College of Genomic Medicine, have already laid out a curriculum, the main roadblock remains: “How do we get to the physicians?”

Turna Ray is the editor of GenomeWeb’s Pharmacogenomics Reporter. She covers pharmacogenomics, personalized medicine, and companion diagnostics. E-mail her here or follow her GenomeWeb Twitter account at @PGxReporter.

 

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FDA Approval for Under-Skin Defibrillator goes to Boston Scientific Corporation

Reporter: Aviva Lev-Ari, PhD, RN

 

Boston Scientific Corporation (BSX) Wins FDA Approval for Under-Skin Defibrillator

 

10/1/2012 7:09:13 AM

 

NATICK, Mass., Sept. 28, 2012 /PRNewswire/ — The U.S. Food and Drug Administration has granted Boston Scientific Corporation (NYSE: BSX) regulatory approval for its S-ICD® System, the world’s first and only commercially available subcutaneous implantable defibrillator (S-ICD) for the treatment of patients at risk for sudden cardiac arrest (SCA). The S-ICD System sits entirely just below the skin without the need for thin, insulated wires — known as electrodes or ‘leads’ — to be placed into the heart. This leaves the heart and blood vessels untouched, offering patients an alternative to transvenous implantable cardioverter defibrillators (ICDs), which require leads to be placed in the heart itself.

 

“The S-ICD System establishes the first new category of cardiac rhythm management devices since the introduction of cardiac resynchronization therapy,” said Raul Weiss, M.D., Associate Professor-Clinical, Cardiovascular Medicine at The Ohio State University. “Doctors now have a breakthrough treatment option that provides protection from sudden cardiac arrest without touching the heart.”

Approval of the S-ICD System was based on data from a 330-patient, prospective, non-randomized, multicenter clinical study, which evaluated the safety and effectiveness of the system in patients at risk of SCA. The S-ICD System met the primary endpoints of the study, and results were presented earlier this year at the Heart Rhythm Society 33rd Annual Scientific Sessions. The study results support that the S-ICD System is an important new treatment option for a wide range of primary and secondary prevention patients.

“With the addition of the S-ICD System, we believe Boston Scientific has a compelling and highly differentiated portfolio that will help fuel our growth strategy,” said Hank Kucheman, chief executive officer, Boston Scientific. “We are the only company to offer an FDA-approved subcutaneous implantable defibrillator and expect this to be the case for several years. The S-ICD System, coupled with our numerous recent regulatory approvals and our other innovative products, such as the WATCHMAN® Left Atrial Appendage Closure Device and Alair® Bronchial Thermoplasty System for the treatment of severe asthma, demonstrates our continued commitment to developing and bringing to market innovative products for physicians and their patients.”

Sudden cardiac arrest is an abrupt loss of heart function. Most episodes are caused by the rapid and/or chaotic activity of the heart known as ventricular tachycardia or ventricular fibrillation. Recent estimates show that approximately 850,000 people in the United States are at risk of SCA and indicated for an ICD device, but remain unprotected.

“Each year, thousands of patients indicated for an ICD are not referred to a specialist and remain untreated,” said William T. Abraham, MD, FACC, Director, Division of Cardiovascular Medicine at The Ohio State University Heart Center. “The S-ICD System is an important new treatment option that has the potential to improve patient acceptance of ICD therapy.”

The S-ICD System is designed to provide the same protection from sudden cardiac arrest as transvenous ICDs. The system has two main components: (1) the pulse generator, which powers the system, monitors heart activity, and delivers a shock if needed, and (2) the electrode, which enables the device to sense the cardiac rhythm and deliver shocks when necessary. Both components are implanted just under the skinthe generator at the side of the chest, and the electrode beside the breastbone. Unlike transvenous ICDs, the heart and blood vessels remain untouched. Implantation with the S-ICD System is straightforward using anatomical landmarks, without the need for fluoroscopy (an x-ray procedure that makes it possible to see internal organs in motion). Fluoroscopy is required for implanting the leads attached to transvenous ICD systems.

Boston Scientific expects to begin a phased launch of the S-ICD System that will expand over time as medical professionals are trained on the safe and effective use of the system. The company acquired the S-ICD System earlier this year when it completed the acquisition of Cameron Health, Inc. The S-ICD System received CE Mark in 2009 and is commercially available in many countries in Europe as well as in New Zealand. To date, more than 1,400 devices have been implanted in patients around the world. To download a high-resolution image of the S-ICD System go to: http://bostonscientific.mediaroom.com/home.

The S-ICD System is intended to provide defibrillation therapy for the treatment of life-threatening ventricular tachyarrhythmias in patients who do not have symptomatic bradycardia, incessant ventricular tachycardia, or spontaneous, frequently recurring ventricular tachycardia that is reliably terminated with anti-tachycardia pacing.

The WATCHMAN device is an investigational device in the United States. It is limited by applicable law to investigational use and not available for sale.

About Boston Scientific
Boston Scientific is a worldwide developer, manufacturer and marketer of medical devices that are used in a broad range of interventional medical specialties. For more information, please visit: www.bostonscientific.com.

Cautionary Statement Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Forward-looking statements may be identified by words like “anticipate,” “expect,” “project,” “believe,” “plan,” “estimate,” “intend” and similar words. These forward-looking statements are based on our beliefs, assumptions and estimates using information available to us at the time and are not intended to be guarantees of future events or performance. These forward-looking statements include, among other things, statements regarding our business plans and growth strategy, markets for our products, regulatory approvals, the importance of the S-ICD System, our technology, clinical trials, product launches, product performance and competitive offerings. If our underlying assumptions turn out to be incorrect, or if certain risks or uncertainties materialize, actual results could vary materially from the expectations and projections expressed or implied by our forward-looking statements. These factors, in some cases, have affected and in the future (together with other factors) could affect our ability to implement our business strategy and may cause actual results to differ materially from those contemplated by the statements expressed in this press release. As a result, readers are cautioned not to place undue reliance on any of our forward-looking statements.

Factors that may cause such differences include, among other things: future economic, competitive, reimbursement, legal and regulatory conditions; clinical trials and outcomes; new product introductions; product performance; demographic trends; intellectual property; litigation; financial market conditions; and future business decisions made by us and our competitors. Such factors are difficult or impossible to predict accurately and many of them are beyond our control. For a further list and description of these and other important risks and uncertainties that may affect our future operations, see Part I, Item 1A Risk Factors in our most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission, which we may update in Part II, Item 1A Risk Factors in Quarterly Reports on Form 10-Q we have filed or will file hereafter. We disclaim any intention or obligation to publicly update or revise any forward-looking statements to reflect any change in our expectations or in events, conditions or circumstances on which those expectations may be based, or that may affect the likelihood that actual results will differ from those contained in the forward-looking statements. This cautionary statement is applicable to all forward-looking statements contained in this document.

CONTACT: Denise Kaigler
508-650-8330 (office)
Media Relations
Boston Scientific Corporation
denise.kaigler@bsci.com
Michael Campbell
508-650-8023 (office)
Investor Relations
Boston Scientific Corporation
investor_relations@bsci.com

SOURCE Boston Scientific Corporation

www.bostonscientific.com

 

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Reporter: Prabodh Kandala, PhD.

A study has identified microRNA-3151 as a new independent prognostic marker in certain patients with acute leukemia. The study involves patients with acute myeloid leukemia and normal-looking chromosomes(CN-AML).

The study by researchers at the Ohio State University Comprehensive Cancer Center — Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC — James) found that when microRNA-3151 (miR-3151) is overexpressed in CN-AML, the disease responds poorly to treatment and patients experience shorter remissions and survival periods. This effect is independent of other gene mutations that may be present in the cells.

Additionally, miR-3151 is encoded within a gene called BAALC, which itself is an independent marker of poor survival when overexpressed in CN-AML.

The findings, published online in the journal Blood (and as a Plenary paper which represents the top 1 to 5 percent of papers published in the print edition of Blood), provide new insights into the nature of AML and might in the future help determine the best therapy for individual patients and further personalize AML therapy.

“Patients with high levels of both miR-3151 and BAALC had the poorest outcome compared with those showing high expression of either miR-3151 or BAALC alone, or those expressing low levels of both,” says principal investigator Dr. Clara D. Bloomfield, a Distinguished University Professor at Ohio State and cancer scholar and senior advisor to the OSUCCC — James. “This suggests that miR-3151 and BAALC may act through different mechanisms to enhance poor outcome of CN-AML patients.”

The study involved 179 patients aged 60 years or older with CN-AML who were treated on Cancer and Leukemia Group B (CALGB) clinical trials.

MicroRNAs are small molecules that cells use to help regulate the kinds and amount of proteins they make. About one-third of human microRNAs are encoded within host genes. Specifically, they are located in the portions of genes called introns, short stretches of DNA that are not used when genetic information is translated to make a protein.

“Very little is known about the regulation of microRNAs located within introns, and especially about their possible interactions with their host genes,” says first author Dr. Ann-Kathrin Eisfeld, a post-doctoral researcher who works in the laboratory of study co-author Dr. Albert de la Chapelle and Bloomfield.

“This is the first description of interplay of an oncogene and its intronic, and possibly oncogenic, microRNA,” Eisfeld says. “It may be the first of other important intronic microRNAs in leukemia and perhaps other malignancies.”

Funding from the National Cancer Institute, the Coleman Leukemia Research Foundation, the Deutsche Krebshilfe-Dr Mildred Scheel Cancer Foundation, the Pelotonia Fellowship Program and the Conquer Cancer Foundation supported this research.

Abstract:

High BAALC expression levels associate with poor outcome in cytogenetically normal AML (CN-AML) patients. Recently, microRNA miR-3151 was discovered in intron 1 of BAALC. To evaluate the prognostic significance of miR-3151expression levels and to gain insight into the biologic and prognostic interplay between miR-3151 and its host, miR-3151 and BAALC expression were measured in pretreatment blood of 179 CN-AML patients. Gene- (GEP) and microRNA-expression (MEP) profiling was performed using microarrays. HighmiR-3151 expression associated with shorter disease-free and overall survival, while high BAALC expression predicted failure of complete remission and shorter overall survival. Patients exhibiting high expression of both miR-3151and BAALC had worse outcome than patients expressing low levels of either gene or both genes. In GEP high miR-3151 expressers showed downregulation of genes involved in transcriptional regulation, post-translational modification and cancer pathways. Two genes, FBXL20 and USP40, were validated as directmiR-3151 targets. In conclusion, high expression of miR-3151 is an independent prognosticator for poor outcome in CN-AML and impacts on different outcome endpoints than its host gene BAALC. The combination of both markers identified a patient subset with the poorest outcome. The described interplay of an intronic miR and its host may have important biologic implications.

http://bloodjournal.hematologylibrary.org/content/early/2012/04/23/blood-2012-02-408492

http://www.sciencedaily.com/releases/2012/05/120514134307.htm

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