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Key Mutation in Acute Myeloid Leukemia (AML) Found

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Scientists have discovered mutations in a particular gene that affects the treatment prognosis for some patients with acute myeloid leukemia (AML), an aggressive blood cancer that kills 9,000 Americans annually.

The Washington University School of Medicine in St. Louis team initially discovered a mutation by completely sequencing the genome of a single AML patient. They then used targeted DNA sequencing on nearly 300 additional AML patient samples to confirm that mutations discovered in one gene correlated with the disease. Although genetic changes previously were found in AML, this work shows that newly discovered mutations in a single gene, called DNA methyltransferase 3A or DNMT3A, appear responsible for treatment failure in a significant number of AML patients. The finding should prove rapidly useful in treating patients and may provide a molecular target against which to develop new drugs. [Read more…]

Genetics Influence Risk of Type 2 Diabetes

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A team led by researchers at the National Human Genome Research Institute (NHGRI),  has captured the most comprehensive snapshot to date of DNA regions that regulate genes in human pancreatic islet cells, a subset of which produces insulin.

The study highlights the importance of genome regulatory sequences in human health and disease, particularly type 2 diabetes, which affects more than 20 million people in the United States and 200 million people worldwide.

“This study applies the power of epigenomics to a common disease with both inherited and environmental causes,”said NHGRI Scientific Director Daniel Kastner, M.D., Ph.D. “Epigenomic studies are exciting new avenues for genomic analysis, providing the opportunity to peer deeper into genome function, and giving rise to new insights about our genome’s adaptability and potential.” [Read more…]

Personalized Blood Tests for Cancer Use Whole Genome Sequencing

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Scientists at the Johns Hopkins Kimmel Cancer Center have used data from the whole genome sequencing of cancer patients to develop individualized blood tests they believe can help physicians tailor patients’ treatments. The genome-based blood tests, believed to be the first of their kind, may be used to monitor tumor levels after therapy and determine cancer recurrence.

“We believe this is the first application of newer generations of whole-genome sequencing that could be clinically useful for cancer patients,” says Victor Velculescu, M.D., Ph.D., associate professor of oncology and co-director of the cancer biology program at Johns Hopkins. “Using this approach, we can develop biomarkers for potentially any cancer patient.”

In a report on the work, published in the February 24 issue of Science Translational Medicine, the scientists scanned patients’ genomes for alterations that, they say, most researchers have not been looking for – rearrangements of large chunks of DNA rather than changes in a single DNA letter among billions of others. They call their new approach Personalized Analysis of Rearranged Ends (PARE).

“In sequencing individuals’ genomes in the past, we focused on single-letter changes, but in this study, we looked for the swapping of entire sections of the tumor genome,” says Bert Vogelstein, M.D., Clayton Professor of Oncology, co-director of the Ludwig Institute at Johns Hopkins, and Investigator in the Howard Hughes Medical Institute. “These alterations, like the reordering of chapters of a book, are easier to identify and detect in the blood than single-letter changes.”

Such DNA rearrangements are widely known to occur exclusively in cancer cells, not normal ones, making them ideal biomarkers for cancer.

Using six sets of cancerous and normal tissue samples taken from four colorectal and two breast cancer patients, the Johns Hopkins team used next-generation sequencing methods to catalogue the genome sequence data of each patient. To find DNA rearrangements, the team first identified regions where the number of DNA copies was more or less than anticipated and where sections of different chromosomes fused together. These regions were further analyzed to identify DNA sequences displaying incorrect ordering, orientation, or spacing. A range of four to 15 rearrangements were found in each of the six samples.

After investigators identified DNA rearrangements in patients’ tumor samples, they looked for the same changes in DNA shed from tumors into the patients’ blood. Using blood samples from two of the colorectal cancer patients, they amplified DNA found in the blood and determined that these tests were sensitive enough to detect rearranged tumor DNA in these samples.

Results from such blood tests, they say, could help clinicians detect cancer or its recurrence and inform them on how a patient is responding to cancer therapies. In one colon cancer patient’s example, the scientists found a section of chromosome four fused to a section of chromosome eight. “We developed a biomarker that could span this rearrangement and used a blood test to evaluate biomarker levels as the patient received a variety of cancer therapies,” says Rebecca Leary, a graduate student at the Johns Hopkins Kimmel Cancer Center.

After an initial surgery, the patient’s biomarker levels dropped due to the removal of the majority of the tumor. The biomarker levels rose again, indicating that additional cancer remained in the patient’s body. After chemotherapy and a second surgery, levels of the biomarker dropped substantially, but still showed a small but measurable level of the biomarker. This was consistent with a small metastatic lesion that remained in the patient’s liver.

The investigators envision that PARE-based biomarkers could also be used to determine whether cancer cells are present in surgical margins or lymph node tissue removed during surgery and possibly for diagnosing early disease. “Eventually, we believe this type of approach could be used to detect recurrent cancers before they are found by conventional imaging methods, like CT scans,” says Luis Diaz, M.D., assistant professor of oncology at Johns Hopkins.

The technology used to examine the patients’ genomes will become inexpensive, predicts Velculescu. He says the genome scan cost them about $5,000 per patient, but that sequencing costs continue to drop. CT scans currently cost $1,500 per scan and are limited in their ability to detect microscopic cancers.

“If current trends in genome sequencing continue, PARE will be more cost effective than CT scans and could prove to be more informative,” says Kenneth W. Kinzler, Ph.D., professor of oncology and co-director of the Ludwig Center at Johns Hopkins.

The Johns Hopkins team plans on testing more patient samples and refining their techniques to produce a commercially viable genome-based blood test. They have filed for patents on the technology.

Under a licensing agreement between the Johns Hopkins University and Genzyme, Velculescu, Vogelstein, and Kinzler, are entitled to a share of royalties received by the University on sales of products related to research described in this paper. The terms of these arrangements are managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.

Funding for the research was provided by the National Institutes of Health, The Lustgarten Foundation, the National Colorectal Cancer Research Alliance, and a UNCF-Merck Fellowship.

Source: Science Translational Medicine, (2/24/2010); John Hopkins Medicine

Researches Find Method to Block Genetic Flaw that Can Cause Muscular Dystrophy

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Researchers have found a way to block the genetic flaw at the heart of a common form of muscular dystrophy. The results of the study, which were published today in the journal Science, could pave the way for new therapies that essentially reverse the symptoms of the disease.

The researchers used a synthetic molecule to break up deposits of toxic genetic material and re-establish the cellular activity that is disrupted by the disease. Because scientists believe that potentially all of the symptoms of myotonic dystrophy – the most common form of muscular dystrophy in adults – flow from this single genetic flaw, neutralizing it could potentially restore muscle function in people with the disease.

“This study establishes a proof of concept that could be followed to develop a successful treatment for myotonic dystrophy,” said neurologist Charles Thornton, M.D., the senior author of the study and co-director of the University of Rochester Medical Center’s Wellstone Muscular Dystrophy Cooperative Research Center. “It also demonstrates the potential to reverse established symptoms of the disease after they have developed, as opposed to simply preventing them from getting worse.”

Myotonic dystrophy is a degenerative disease characterized by progressive muscle wasting and weakness. People with myotonic dystrophy have prolonged muscle tensing (myotonia) and are not able to relax certain muscles after use. The condition is particularly severe in the hand muscles and can cause a person’s grip to lock making it difficult to perform rapid, repeated movements. Currently there is no medication to halt the progression of the disease.

Toxic RNA Holds Proteins Hostage
Although the genetic flaw that causes myotonic dystrophy was discovered in 1992, researchers studied the defect for many years before they had a clear understanding of the molecular events that ultimately produce the symptoms of the disease. Over time it became apparent that a central player in myotonic dystrophy was RNA, a versatile molecule that is very similar to DNA. RNA serves a vital function by relaying the genetic information from the nucleus – the protected area of the cell that houses DNA –out to the main body of the cell, where the instructions are used to build proteins. Every gene produces its own RNA, usually in multiple copies, and every RNA is a genetic blueprint of its parent gene.

The surprising aspect of myotonic dystrophy was that the genetic defect leads to production of a toxic RNA – the first example in human genetics in which RNA was cast in the role of molecular perpetrator. The errant RNA has a toxic effect because it grabs onto and holds hostage certain proteins, preventing them from carrying out their normal functions. For example, the capture of a protein called “muscleblind” causes the locking grip phenomenon that is a hallmark of the disease, a sign of faulty electrical control in muscle cells. Over time, the toxic RNA is produced in abundance and the captive proteins accumulate in deposits – or inclusions – that are visible in the cell’s nucleus.

“An unexpected byproduct of research on myotonic dystrophy was that we were forced to change our ideas about the role of RNA in genetic disease,” said Thornton. “Once we adjusted to this new concept, we realized that the prospects for developing treatment might be unusually good. No essential component of muscle is missing, but some important proteins are in the wrong place, stuck on the toxic RNA.”

New Tools to Tackle Genetic Flaws
The Rochester team used a synthetic molecule – called an antisense morpholino oligonucleotide – that mimics a segment of the genetic code. In this case the morpholino was specifically designed to bind to the toxic RNA and neutralize its harmful effects by releasing the captured proteins. When injected into the muscle cells of mice with myotonic dystrophy the molecule found its way to the cell nucleus, broke up the deposits of toxic RNA, freed the captive muscleblind proteins, and ultimately improved the function of the muscle cells.

The researchers specifically observed a restoration of proper electrical control in the cells, which is a convenient way to monitor the condition. However, because the hostage proteins play a role in a myriad of other cellular functions, they believe that this treatment will ultimately alleviate other aspects of the disease as well.

“Based on our current understanding we would predict that by releasing the proteins held hostage, many of the symptoms of the disease may potentially be corrected by this approach,” said URMC neurologist Thurman Wheeler, M.D., co-author of the study.

These genetic tools are relatively new and have provided researchers with a heretofore unprecedented ways to precisely target and manipulate genetic activity. “The current textbooks for medical students do not have chapters on antisense oligonucleotides, but this will change in the near future,” said Thornton. “As compared to conventional drugs that work on proteins, antisense oligonucleotides work on RNA. They have been around for 20 years, but only recently is their full potential being realized. They provide great flexibility and they can be developed rapidly.”

The authors are quick to point out that major hurdles must be overcome before this compound can be tested in humans. Specifically, a better delivery system must be developed to get this or a similar compound to where it needs to go in the body, and the potential side effects must be carefully analyzed. However, having established a general concept of what a treatment for myotonic dystrophy may look like, researchers believe that the next steps in developing an effective drug should go faster.

Source: Science, July 16, 2009

Chemotherapy Drug Resistance Linked to Genetic Variant in Women with Breast Cancer

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Researchers have found links between an individual’s genetics and their response to treatment with chemotherapy. The findings, by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, and colleagues, show how a genetic variant, located in the SOD2 gene, may affect how a person responds to the chemotherapy drug cyclophosphamide. Cyclophosphamide is used in the treatment of breast and other cancers.

The SOD2 gene produces a key protein that protects cells from damage by molecules known as reactive oxygen species, or free radicals. Reactive oxygen species are produced by normal cellular processes and the action of some chemotherapy drugs. The findings represent the first preliminary evidence pointing toward a mechanism and a potential biomarker for cyclophosphamide resistance in breast cancer patients. The study appeared online June 9, 2009, in Clinical Cancer Research.

“This study shows how, with the progress of individualized medicine, a diagnostic test may be developed that determines whether a patient has certain genetic variations that may modify the effect of certain chemotherapies,” said study author Sharon Glynn, Ph.D., of NCI’s Center for Cancer Research.

“In the future, such tests may be used to guide the treatment of patients with the SOD2 variation, ensuring that they receive a therapy that is more effective than cyclophosphamide-based therapies,” added senior author Stefan Ambs, Ph.D., also of the Center for Cancer Research.

Most genes in human cells are present in two copies — one inherited from the mother and the other inherited from the father. These gene copies can vary from one another. Some variations in genes play an important role in how a gene is expressed or how its protein product functions.

The variant identified by the researchers in the SOD2 gene affects both the structure and the function of the encoded protein, an enzyme known as manganese superoxide dismutase (MnSOD) and affects the ability of MnSOD to reach its proper location in the cell and its activity level. MnSOD normally functions inside cellular compartments known as mitochondria and helps protect cells from damage caused by reactive oxygen species formed during cellular metabolism. Excessive levels of reactive oxygen species can be toxic to cells. Indeed, some anticancer drugs depend on increased production of reactive oxygen species to kill cancer cells. Furthermore, some studies have indicated that, because MnSOD neutralizes reactive oxygen species, it can modify the effects of chemotherapy drugs. For example, in laboratory and animal models, increased activity of MnSOD protects cells against the toxic effects of doxorubicin, which is a widely used anticancer drug.

In the new study, the research team investigated whether the variation affected survival in two separate groups of women with breast cancer: 248 women in the United States and 340 women in Norway. Some of the women received chemotherapy, and some did not receive chemotherapy. The team first analyzed DNA from the women to determine their genotype, meaning which types of the SOD2 gene they had. The researchers found that, among patients who received chemotherapy, those who had one form had decreased survival and those with another form had the poorest survival. In contrast, the genotype of SOD2 did not affect survival among those who did not receive chemotherapy.

Next, the team looked at the relationship between SOD2 genotype and the type of chemotherapy the women received. The data were analyzed according to which of three types of commonly used chemotherapy drugs were administered: doxorubicin, 5-fluorouracil, or cyclophosphamide. Both doxorubicin and cyclophosphamide generate reactive oxygen species in cancer cells during treatment. The researchers determined that the presence of a particular variant was associated with decreased survival of patients treated with chemotherapy regimens that contained any of the three drugs. However, the most significant effects were found with the drug cyclophosphamide. Women with a distinct variant form of SOD2 and who received cyclophosphamide-containing chemotherapy had the poorest survival.

The research team says more work is necessary to confirm these findings and to examine the precise mechanism by which a genotype influences the response of cancer cells to cyclophosphamide. The team plans to examine the influence of several variations on the resistance to other chemotherapies.

Source: National Institutes of Health (NIH), 6/9/2009

Early Detection of Digestive Cancers in Multiple Organs with DNA Stool Test

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Mayo Clinic researchers have demonstrated that a noninvasive screening test can detect not only colorectal cancer but also the common cancers above the colon — including pancreas, stomach, biliary and esophageal cancers.

Gastrointestinal (GI) cancers account for approximately one in four cancer deaths. While high cure rates can be achieved with early-stage detection for each type, only colorectal cancer is currently screened at the population level. Most people associate colorectal cancer screening with invasive colonoscopy, but previous Mayo Clinic research has shown that stool DNA testing can identify both early-stage colorectal cancer and precancerous polyps. Researchers are now studying the use of noninvasive stool DNA testing to detect lesions and cancer throughout the GI tract.

“Patients are often worried about invasive tests like colonoscopies, and yet these tests have been the key to early cancer detection and prevention,” says David Ahlquist, M.D., Mayo Clinic gastroenterologist and lead researcher on the study. “Our research team continues to look for more patient-friendly tests with expanded value, and this new study reveals an opportunity for multi-organ digestive cancer screening with a single noninvasive test.”

The researchers studied 70 patients with cancers throughout the digestive tract. Besides colon cancer, the study looked at throat, esophagus, stomach, pancreatic, bile duct, gallbladder and small bowel cancers to determine if gene mutations could be detected in stool samples. Using a stool test approach developed at Mayo Clinic, researchers targeted DNA from cells that are shed continuously from the surface of these cancers. Also studied were 70 healthy patients. Stool tests were performed on cancer patients and healthy controls by technicians unaware of sample source. The stool DNA test was positive in nearly 70 percent of digestive cancers but remained negative for all healthy controls, thus demonstrating the approach’s feasibility.

Stool DNA testing detected cancers at each organ site, including 65 percent of esophageal cancers, 62 percent of pancreatic cancers, and 75 percent of bile duct and gallbladder cancers. In this series, 100 percent of both stomach and colorectal cancers were detected. Importantly, stool test results did not differ by cancer stage; early-stage cancers were just as likely to be detected as late-stage cancers.

“It’s very exciting to see this level of sensitivity for digestive cancer detection in our first look at this test application,” says Dr. Ahlquist, “Historically, we’ve approached cancer screening one organ at a time. Stool DNA testing could shift the strategy of cancer screening to multi-organ, whole-patient testing and could also open the door to early detection of cancers above the colon which are currently not screened. The potential impact of this evolution could be enormous.”

In October 2008, this Mayo Clinic research team published results of a multicenter study using first-generation stool DNA testing. In the seven-year, multicenter study (Ann Intern Med 2008;149:441-50), researchers found that the first-generation stool DNA tests were better than fecal blood tests for detecting cancer and precancerous polyps of the colon.

In January 2009 (Gastroenterology 2009;136:459-70), Mayo researchers published some technical improvements that nearly doubled the sensitivity of stool DNA testing for detecting premalignant polyps and increased cancer detection to about 90 percent, which is the approximate rate of detection observed for CT colonography.

Researchers hope that the next generation tests will have significant improvements in accuracy, processing speed, ease of patient use and affordability. “We anticipate that next generation tests will also be able to predict the tumor site, which will help physicians direct diagnostic studies and minimize unnecessary procedures,” says Dr. Ahlquist.

Source: Mayo Clinic, June 2, 2009

Researchers Develop DNA Compounds that May Help Treat Lupus

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A research team led by a University of Iowa investigator has generated DNA-like compounds that effectively inhibit the cells responsible for systemic lupus erythematosus — the most common and serious form of lupus. There currently is no cure for this chronic autoimmune condition that damages the skin, joints and internal organs and affects an estimated one million Americans.

The team, which included researchers at Boston University School of Medicine, demonstrated the anti-inflammatory effects of class R inhibitory oligonucleotides in laboratory experiments. The findings, which could eventually lead to new treatments, appear May 28 in BioMed Central’s open access journal Arthritis Research and Therapy.

“The increased potency of class R inhibitory oligonucleotides for certain cells involved in lupus flare-ups could help patients by providing specific inhibition, yet allowing them to generate a protective immune response when needed,” said the study’s lead author, Petar Lenert, M.D., Ph.D., assistant professor of internal medicine at the University of Iowa Roy J. and Lucille A. Carver College of Medicine.

During periodic flare-ups in people with lupus, the immune system overreacts and mistakenly attacks cells and tissues throughout the body, resulting in a range of symptoms including inflammation, pain and a characteristic “butterfly rash” across the cheeks.

Using human cell lines and isolated mouse cells, Lenert and his colleagues showed that the DNA-like compounds were able to selectively reduce the activity of two types of immune cells called autoreactive B cells and dendritic cells. When given to mice with lupus, the compounds delayed death and reduced kidney damage, proving their effectiveness.

“With further testing, we hope that class R inhibitory oligonucleotides may become another weapon in the fight against lupus,” Lenert said.

Lupus prevalence varies by country and ethnicity. It is much more common in women than men; nine out of 10 people with lupus are female. Lupus also is three times more common in African-American women than in Caucasian women and is more prevalent in women of Latino, Asian and Native American descent.

The study received grants from the National Institutes of Health and the Alliance for Lupus Research.

Source: University of Iowa Health Sciences, May 27, 2009

Genetic Link Between Heart Disease and Gum Disease

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BBC News reports that a genetic link between gum disease and heart attacks has been found by researchers in Germany.
Periodontitis (gum disease) is known to be associated with heart disease but how exactly they are linked is unknown.

Now the University of Kiel team has found a common gene mutation in people with periodontitis and heart attack patients, a conference heard.

Source: BBC, May 25, 2009
news.bbc.co.uk/1/hi/health/8063512.stm

Research Team Discovers Gene-Silencing Technology

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Genes that can cause certain diseases can be silenced by a new technology that could help prevent disease where gene dysfunction is involved. The research was led by Ming-Ming Zhou, Ph.D., Professor and Chairman of the Department of Structural and Chemical Biology at Mount Sinai School of Medicine.

“By being able to silence certain genes, we may be able to suppress genes that can cause diseases such as HIV/AIDS, cancer, inflammation and diseases of the central and peripheral nervous systems. We now know we can focus on these genes and potentially change the ultimate course of many diseases that have a major impact on people’s lives,” says Dr. Zhou.

Dr. Zhou, Shiraz Mujtaba, Ph.D., Assistant Professor of Structural and Chemical Biology at Mount Sinai and their colleagues found that Paramecium bursaria chlorella virus uses a viral protein to modify host DNA packing chromatin and switch host transcription machinery for viral replication. Using this information, the doctors developed a new technology capable of suppressing transcriptional expression of targeted genes in human cells, including genes that are linked to the onset of a number of diseases.

Source: Nature Cell Biology, September, 2008

Researchers ID Genetic Variants Linked to Increased Risk of Metabolic Syndrome

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Nutrition researchers have identified five common genetic variations that increase the risk of metabolic syndrome, a group of factors linked to heart disease and diabetes. Another variant they found appeared to protect against the condition.

People with metabolic syndrome have at least three of the following symptoms: abdominal obesity, high blood triglyceride levels, lower good cholesterol (HDL), elevated blood pressure and elevated fasting blood glucose. They are four times as likely to develop heart disease and at least seven times more likely to develop diabetes as individuals without metabolic syndrome.

The investigators at Washington University School of Medicine in St. Louis looked for changes in the CD36 gene, which is located in a region of chromosome 7 that has been linked to metabolic syndrome in several genome-wide studies.

The researchers say linking changes in the CD36 gene to the risk for metabolic syndrome and abnormal levels of good cholesterol is important because as more people in the United States become obese, they also become susceptible to these problems. Better understanding of the relationships between obesity, the gene and disease risk may allow for earlier identification of individuals who are more susceptible to develop metabolic syndrome. Treatments such as medication or lifestyle changes could begin earlier, perhaps preventing or delaying future problems with diabetes or heart disease.

Senior investigator Nada A. Abumrad, Ph.D., the Dr. Robert C. Atkins Professor of Medicine and Obesity Research, first identified the CD36 protein in studies with mice. Her research has demonstrated that the protein facilitates the use of fatty acids for energy. CD36 is located on the surface of cells and distributed throughout many tissues, including fat cells, the digestive tract, heart and skeletal muscle.

The investigators focused on 36 small genetic variations, called single nucleotide polymorphisms (SNPs), in the CD36 gene. A SNP involves a single base-pair change in the DNA.

The team evaluated DNA taken from more than 2,000 African-Americans because variations in the gene are more common in individuals of African and Asian descent than in other racial groups. The researchers expect, however, that these findings also will be applicable in other populations.

“The idea was to look at the different variations in the gene and see whether they were more prevalent in people who also had elevated cholesterol, abnormal blood glucose or the other components of the metabolic syndrome,” says first author Latisha Love-Gregory, Ph.D., research instructor in the Division of Geriatrics and Nutritional Science.

Love-Gregory says the research team demonstrated an association between SNPs in the gene and metabolic syndrome.

“There is additional work to do to determine if the function of these genetic variants actually contributes to the development of type 2 diabetes or heart disease,” she explains. “We do expect that a number of different changes, in both CD36 and other genes, will be related to these diseases. What we’d like to learn, however, is whether the changes identified in the gene alter the CD36 protein in ways that change its function to make a person more vulnerable.”

The team determined that five of the SNPs they examined are more common in people who have symptoms of metabolic syndrome, but a sixth seemed to have a more favorable metabolic effect. The “protective” SNP makes people produce lower amounts of CD36 protein.

Humans have two copies of each chromosome. In this study, people who had the protective variant on only one of their copies of chromosome 7 were less susceptible to metabolic syndrome. But people with two copies of the variant, who were completely deficient in the CD36 protein, did not appear to be protected. They tended to have lower levels of HDL, the so-called good cholesterol.

“A bit less CD36 protein may improve your risk profile, but people need some CD36 function,” Abumrad says. “It’s like requiring a certain level of fat in the diet. Fatty acids are important for optimal function of many tissues — from pancreatic beta cells to skeletal muscle to the heart — but too much fat creates a problem.”

Love-Gregory and Abumrad found that many variants influenced blood levels of HDL cholesterol. Now they are taking a closer look at the relationship between CD36 and HDL cholesterol. Higher levels of HDL normally are considered positive, but because changes in the CD36 gene seem to influence HDL, the researchers want to make sure that the HDL molecule isn’t being altered in composition or function.

“We’re going to follow up on the HDL component of the study,” Love-Gregory says. “We’re also going to look for additional variants in the promoter region of the gene that controls how the gene is regulated. And we’re planning to look for evidence of these gene variants and their associations with HDL and the metabolic syndrome in other populations and ethnic groups.”

Source: Human Molecular Genetics, June, 2008