Category Archives: Gene Medicine

Public release date: 15-Feb-2012
[ | E-mail | Share ]

Contact: Marjorie Montemayor-Quellenberg
mmontemayor-quellenberg@partners.org
617-534-2208
Brigham and Women's Hospital

BOSTON, MA?Mutations in TTN?the largest gene in the human genome?cause idiopathic (unknown cause) dilated cardiomyopathy (DCM), a common form of heart failure, according to a study by Brigham and Women's Hospital (BWH) researchers. The TTN gene encodes a protein that functions as a scaffold for assembly of contractile proteins in muscle cells and also regulates the production of force in cardiac muscle cells.

Because of its enormous size, the TTN gene was, until recently, too difficult to sequence and analyze in large numbers of patients. But with the development of next-generation sequencing technologies, the time was ripe to tackle TTN. Christine Seidman, MD, BWH Cardiovascular Genetics Center director and a team of dedicated scientists at Harvard Medical School; Imperial College, London; University of Colorado; and physicians at BWH took on the challenge to comb through the gigantic gene. Their study unveils how mutated TTN genes can lead to structural deformations in heart muscle fibers, which may then lead to heart muscle disease. The study will be published in the February 16, 2012 issue of The New England Journal of Medicine.

Researchers analyzed genetic samples from 312 people diagnosed with DCM, 231 with another heart muscle disease called hypertrophic cardiomyopathy (HCM), and 249 people without heart disease. They identified 72 mutations in the TTN gene that foreshorten the encoded protein. These shortened titin proteins lack regions involved in regulating force production in heart cells. Many more mutations were found in those with DCM compared to healthy individuals and those with HCM, indicating that TTN gene mutation causes DCM, but rarely causes HCM.

Moreover, the study notes that outcomes of patients with DCM were similar regardless of whether or not a person has a TTN gene mutation. However, among those that did have TTN mutations, adverse events such as cardiac transplantation, implantation of a ventricular assist device, or death occurred earlier in men than women. Seidman believes that the study findings will help improve future diagnosis and treatment of heart diseases.

"Early diagnosis of any disease, including DCM, can allow interventions that may prevent some of the devastating outcomes, such as sudden cardiac death from an arrhythmia or development of heart failure," said Seidman. "By knowing that TTN mutations account for a substantial amount of idiopathic DCM, we now will have the opportunity for early diagnosis in lots of at-risk individuals, and any person who has a family member with idiopathic DCM."

###

This research was supported by funding from Howard Hughes Medical Institute; National Institutes of Health Leducq Foundation; American Heart Association and Muscular Dystrophy Association; UK National Institute for Health Research Cardiovascular Biomedical Research Unit (Royal Brompton and Harefield NHS Foundation Trust & Imperial College), The British Heart Foundation and the MRC UK; and J. Ira and Nicki Harris Family Research Award.

Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare, an integrated health care delivery network. BWH is the home of the Carl J. and Ruth Shapiro Cardiovascular Center, the most advanced center of its kind. BWH is committed to excellence in patient care with expertise in virtually every specialty of medicine and surgery. The BWH medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in quality improvement and patient safety initiatives and its dedication to educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Biomedical Research Institute (BRI), http://www.brighamandwomens.org/research, BWH is an international leader in basic, clinical and translational research on human diseases, involving more than 900 physician-investigators and renowned biomedical scientists and faculty supported by more than $537 M in funding. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative. For more information about BWH, please visit http://www.brighamandwomens.org.

[ | E-mail | Share ]

AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.

Here is the original post:
Mutations in gigantic gene responsible for common heart muscle disease

WEDNESDAY, Feb. 15 (HealthDay News) -- Researchers report that they've discovered the importance of a particular gene in kicking off puberty in humans, a finding that offers insight into how the mysterious process begins and could help children who suffer from a rare disease that prevents the start of puberty.

An analysis of the DNA of a family whose members have suffered from the disease confirmed that the gene is vital because it paves the way for the body to process a hormone known as kisspeptin.

"Without kisspeptin, a human being cannot attain sexual characteristics of his/her gender and child-bearing capacity. Kisspeptin is absolutely required for the start of the puberty process in humans," said study author Dr. A. Kemal Topaloglu, of the department of pediatric endocrinology at Cukurova University in Adana, Turkey.

A mutation in the gene, the researchers found, can cause a rare condition called hypogonadotropic hypogonadism, in which children don't fully enter puberty.

Dr. William F. Crowley Jr., director of the Harvard Reproductive Endocrine Sciences Center at Harvard Medical School, said the condition affects no more than one in 10,000 children, and perhaps even fewer.

"They look like they're 12 years old, even when they're 20. They don't have a growth spurt and tend to be short, and the males don't shave," Crowley said.

In the new study, researchers examined the genetic makeup of a family in which four daughters had the disease. They linked the disease to a mutation in the gene that creates a receptor that processes the kisspeptin hormone.

The hormone can be used to make the brain produce hormones that stimulate the maturation of ovaries and testicles, Topaloglu said. Also, medications that shut down the hormone could be used to treat a condition that causes early puberty, he said, or serve as a contraceptive.

"Such drugs can also be used in the treatment of cancers that are stimulated by sex hormones, the most notably breast and prostate cancers," Topaloglu said.

The research could lead to alternative treatments for the puberty-preventing disease. Currently, hormone therapy is almost always a success when used to treat kids with the condition, but it's more difficult to enable them to have children of their own once they grow up, Topaloglu said.

As for the big question of what causes puberty, Crowley said the new findings help provide another clue. They show how the gene -- one of 19 -- helps turn on the pilot light that powers puberty, he said.

"This is a very rare cause of a very rare condition," he said. "But every piece of this puzzle winds up being very important to putting the whole thing together."

The study appears in the Feb. 16 issue of The New England Journal of Medicine.

More information

For more about puberty and adolescence, try the U.S. National Library of Medicine.

Here is the original post:
Gene Linked to Start of Puberty

WEDNESDAY, Feb. 15 (HealthDay News) -- Researchers have discovered a defective gene that's responsible for more than one-quarter of cases of inherited dilated cardiomyopathy, a serious heart muscle disease that often leads to heart failure by middle age.

In the study, published in the Feb. 16 issue of the New England Journal of Medicine, researchers analyzed the DNA of 312 people with dilated cardiomyopathy, 231 people with another form of heart muscle disease (called hypertrophic cardiomyopathy) and 249 people with healthy hearts.

The study patients with dilated cardiomyopathy had no obvious cause for their disease -- such as alcoholism, heart attacks and other infections -- so the researchers believed there was a genetic origin for the disease in these patients.

About 27 percent of the dilated cardiomyopathy patients had mutations on the TTN gene that shortened the length of the gene.

Only 1 percent of the patients with the other form of cardiomyopathy and 3 percent of patients with healthy hearts had similar mutations, the investigators found.

Further analysis of family members' DNA revealed that up to half of the dilated cardiomyopathy patients had first-degree relatives (including parents and siblings) who also had the TTN mutation by age 40, and of those, nearly all (95 percent) had some sign of heart disease, said study co-leader Jonathan Seidman, a professor of genetics at Harvard Medical School.

Seidman's wife, Dr. Christine Seidman, a professor of genetics and a cardiologist at Harvard, was the other study co-leader.

The researchers also estimate that about 20 percent of sporadic cases of the disease, that is, dilated cardiomyopathy that isn't passed down from parents, involve a TTN mutation.

In dilated cardiomyopathy, the chambers of the heart become enlarged, the walls thin and the ability of the heart to pump is impaired. When the heart can't squeeze properly, it can't circulate enough blood, leading to heart failure and landing many people on heart transplant lists.

Prior research has found genetic causes for dilated cardiomyopathy, but collectively those genes account for only about one-fifth of cases, Seidman said.

TTN is a very large gene, which made it difficult to analyze until recently, Seidman explained. The protein that TTN makes contains 30,000 amino acids, while the average protein contains about 1,000 amino acids. Only with the advent of next-generation gene sequencing -- which allows for more genetic data to be analyzed more quickly and for less money -- did it become possible to effectively analyze TTN, he said.

In people with a shortened TTN gene, the protein that's produced causes problems with the filaments inside the muscle fibers that allow the heart to contract.

The few people with healthy hearts who had a similar mutation and didn't have the disease had the shortening on a different location of the gene.

"Not only do they [the people with dilated cardiomyopathy] have the shortened mutation, it has to occur in just the right place," Seidman said.

The analysis also found that men with the TTN mutation are affected more severely than women. "We don't know why," Seidman said, noting that for other causes of heart failure, men also tend to get sicker younger and more severely than women.

To develop dilated cardiomyopathy, children have to inherit just one copy of the mutated TTN gene from a parent, the researchers noted.

Dr. Gordon Tomaselli, president of the American Heart Association and chief of cardiology at Johns Hopkins Medicine in Baltimore, said the study is important for both researchers and patients.

"Of the cases that are inherited [dilated cardiomyopathy], it looks like a substantial proportion are due to mutations in the TTN gene," Tomaselli said.

Currently, genetic tests are available that screen for the other known causes of cardiomyopathy. Soon, possibly within months, expect to see TTN testing added to genetic panels, Tomaselli said.

Although there is no cure for dilated cardiomyopathy, patients who know early on that they are susceptible can take steps to keep their hearts healthier longer, he noted. That may include taking certain heart failure medications, maintaining blood pressure control and other lifestyle changes.

An estimated one-third to one-half of dilated cardiomyopathy cases have a genetic cause, Tomaselli added. The others have an environmental trigger, such as drug or alcohol abuse or infections. For those patients, TTN would likely not play a role in the disease.

More information

The U.S. National Heart, Lung, and Blood Institute has more on cardiomyopathy.

Read the original:
Study Finds Gene Behind Inherited Cases of Enlarged Heart

The researchers used gene therapy in rats to stimulate production of somatostatin, a seizure-stopping chemical that naturally occurs in the brain. The study was published in the February issue of the journal Neuroscience Letters.

More than 3 million people in the United States have epilepsy, according to the Centers for Disease Control and Prevention. This lifelong disease is characterized by uncontrollable seizures and can keep people from living independently or holding jobs, particularly if they do not respond to seizure-controlling medication. Finding novel ways to prevent these seizures could help people with epilepsy live more normal, symptom-free lives, said Dr. Paul Carney, chief of the division of neurology in the UF College of Medicine department of pediatrics and senior author of the study.

“For years people have focused only on treating the disease, not preventing the disease,” Carney said. “The mantra is no seizures, no side effects.”

People with epilepsy tend to have lower levels of the hormone somatostatin, as do people with Alzheimer’s disease. Although somatostatin, which belongs to a group of protein-like molecules called neuropeptides, is present in the brains of people with epilepsy, scientists have shown that its levels decrease during seizures, said Rabia Zafar, the lead author of the paper and a former postdoctoral associate in Carney’s lab.

To test whether they could prevent seizures by bolstering levels of this hormone, the researchers administered a dose of the gene that triggers somatostatin expression. A harmless virus transported the gene safely through the body.

“There is some somatostatin in the brain anyway, because it’s a neuropeptide, but there was a dramatic increase after the injection,” Zafar said.

Boosting somatostatin levels led to weaker and shorter seizures, and none of the subjects that received the injection suffered the highest level of seizure. Better yet, the treatment did not result in unwanted side effects. The only side effect was positive: subjects learned better after the treatment.

“Being able to restore somatostatin up to normal levels allows the brain to heal itself and that is the idea here,” Carney said. “We’re putting something back in that is normally there and allowing the brain to pick it up as part of its normal machinery. We’re not putting in a drug.”

In addition to epilepsy, studies have shown that somatostatin may play a role in aging and neurodegenerative disorders such as Alzheimer’s disease, Carney said. Somatostatin is a neuromodulator, which means it can alter how nerve cells behave.

In this study, the researchers focused on temporal lobe epilepsy, the most common form of the disease. Although medication helps control seizures in most people with this type of epilepsy, about 30 percent of patients do not respond to therapy, Carney said.

“We need better, more effective treatments for a large population of children and adults who don’t respond to conventional treatments,” he said. “Gene therapy, as well as other forms of treatment, are emerging, and there is the hope and promise they will offer more effective and novel treatments for people with drug-resistant epilepsy.”

But the researchers caution that this study is just a first step. Additional research is needed before the technique can be attempted in humans. Researchers are particularly focused on ensuring the treatment does not cause inflammation and discovering the best way to administer it, either be injection to the brain or a less invasive intravenous infusion.

“What effect a compound is going to have partly depends on where in the seizure circuit that new compound or gene is being placed. You could put the same chemical in two places and get two different results,” said Dr. Edward Bertram III, a professor of neurology at the University of Virginia, who was not involved in the study. “That is going to be the issue as they try to develop this: Where should we be putting this to have the best effect? On the promising side, they put (the gene) in a restricted area and had an effect. That is a great first step.”

Provided by University of Florida (news : web)

Originally posted here:
Gene therapy for epilepsy could stop seizures

For Immediate Release:
Feb. 13, 2012

Newswise — BOSTON—Novel gene abnormalities discovered in a subpopulation of lung and colorectal tumors could potentially identify patients with a good chance of responding to highly specific “targeted” drugs already in use for treating other cancers, scientists report.

The genetic alterations – pieces of two genes fused together - showed up in a massive search of the DNA in stored tumor samples of non-small cell lung cancer and colorectal cancer, said researchers from Dana-Farber Cancer Institute and Foundation Medicine, Inc. These specific genetic abnormalities had not been previously linked to the two cancer types.

Their results were published online by the journal Nature Medicine.
Other cancers with similar genetic alterations often respond to “targeted” drugs s that block overactive proteins called tyrosine kinase inhibitors. This suggests that the same drugs also may be effective against lung and colorectal tumors driven by the newly found gene fusions. Because these drugs are already approved to treat cancer, it should be possible to move rapidly to clinical trials in colorectal and lung cancer, the authors said.

If the trials are successful, physicians could potentially test patients' tumors for the presence of the gene fusions and prescribe a medication matched to those alterations, said Pasi A. Jänne, MD, PhD, a thoracic oncologist at Dana-Farber and co-senior author of the report along with Philip J. Stephens, PhD, and Maureen Cronin, PhD, of Foundation Medicine. Doron Lipson, PhD, is the paper’s first author.
“This is a textbook example of personalized medicine for lung cancer – a genetic alteration found in a subset of patients that we can now look for and use as a means to select particular therapies,” Jänne said.

“In the past, although these targeted drugs were available, they were not chosen for a particular subset, but instead given to everybody,” he explained. “This will increase the likelihood of those therapies being more successful.”

The researchers estimate that less than 1 percent of Caucasians and about 2 percent of Asians with lung cancers carry this alteration – a fusion gene labeled KIF5B-RET. However, they said the finding opens a significant therapeutic opportunity.

“In a common indication like non-small cell lung cancer, identifying even a small subpopulation of individuals with gene fusions who may be responsive to a targeted therapy has the potential for major therapeutic impact,” said Stephens, executive director of cancer genomics at Foundation Medicine. “This joint research with Dana-Farber translates genomic research to the clinic and we expect that it may quickly have a positive impact for patients.”

The American Cancer Society projects that 226,160 Americans will be diagnosed with lung cancer in 2012 and 160,340 will die of the disease.

Foundation Medicine scientists identified the novel fusion gene in a DNA tumor sample removed from a 44-year-old man with non-small cell lung cancer (NSCLC) who had never smoked. The hybrid gene is composed of a piece of a cell growth gene, RET, and part of another gene, KIF5B. This abnormal gene combination causes RET to act like a growth switch stuck in the “on” position, spurring uncontrolled cell division.

The company formed a collaboration with Jänne and his Dana-Farber colleagues to follow up the discovery. “We looked for the RET fusion gene in a larger collection of lung tumor samples to determine how common it is, and if it is acting as an oncogene [a gene that drives cancer]” said Jänne. They searched samples from 121 Caucasian patients and 405 Asian patients who had never smoked or had rarely smoked in the past.
The RET fusion gene was detected in 1 of the Caucasian samples (0.8 percent) and 9 of the Asian patient samples (2 percent).

Thyroid cancers containing RET gene hybrids are known to respond to certain targeted drugs that inhibit RET. When Dana-Farber investigators tested three such inhibitors – sorafenib, sunitinib and vandetinib – on cultured cells containing the newly discovered RET mutation, each of the drugs killed those cells, the scientists reported.
Jänne noted that some patients with NSCLC have responded to treatment with these inhibitor drugs. The researchers want to find out whether those patients had RET mutations in their tumors.

The Foundation Medicine scientists also sequenced DNA samples from 40 patients with colorectal cancer. Along with numerous known mutations, the researchers identified a novel gene alteration, C2orf44-ALK, that causes a 90-fold overexpression of the ALK protein leading to cancerous proliferation. Overexpressed ALK is also found in a small percentage of lung cancer cases and can be inhibited by the targeted drug crizotinib. This raises the possibility of using crizotinib to target the C2orf44-ALK fusion gene in colorectal cancer, the researchers said.

In addition to Cronin, Jänne, Lipson and Stephens, the paper’s co-authors were from Sharett Institute of Oncology, Jerusalem; TEVA Pharmaceutical Industries, Petach Tikva, Israel; Samsung Medical Center, Seoul, Korea; Nagoya City University Graduate School of Medical Sciences, Japan; Asan Medical Center, Seoul, Korea; and Albany Medical Center, New York.

The research was funded in part by the Dana-Farber/Harvard Cancer Center Lung Cancer SPORE grant from the National Cancer Institute and the Cammarata Family Foundation Research Fund.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women’s Hospital as Dana-Farber/Brigham and Women’s Cancer Center and it provides pediatric care with Children’s Hospital Boston as Dana-Farber/Children’s Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding. Follow Dana-Farber on Twitter: @danafarber or Facebook: facebook.com/danafarbercancerinstitute.

EDITOR’S NOTE: This video is available online at:
http://resources.dana-farber.org/pr/media/

# # #

Comment/Share

See more here:
Newly Identified Fusion Genes in Lung and Colorectal Cancer May Guide Treatment with "Targeted" Drugs

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Researchers from Foundation Medicine and the Dana Farber Cancer Institute have demonstrated that Foundation's sequencing-based assay, which it is developing for cancer diagnostics, can identify clinically actionable mutations from tumor samples.

Reporting in Nature Medicine this week, the team tested the assay on 40 colorectal cancer and 24 non-small cell lung cancer formalin-fixed paraffin-embedded biopsy samples and identified at least one potentially clinically actionable alteration in 59 percent of the samples.

Additionally, the test identified two novel gene fusions.

"These findings in aggregate show the potentially large clinical impact of a single multiplex test that requires minimal DNA from FFPE tumor biopsies," the authors wrote in the paper.

The company recently received CLIA certification from the Centers for Medicare and Medicaid Services for its genomic sequencing lab in Cambridge, Mass., and plans to commercialize its test this year.

The test analyzed 2,574 exons from 145 genes that are associated with cancer-related pathways, targeted therapy, or prognosis, plus 37 introns from 14 genes that are frequently rearranged in cancer. Sequencing was done on the Illumina platform to an average 229-fold coverage.

In the 40 colorectal cancer samples, 125 alterations were identified in 21 genes, with 39 out of 40 samples having at least one mutation. Eighty percent of the samples had mutations to TP53, a known tumor suppressor that is mutated in a broad range of cancers, and 67.5 percent of the samples had mutations to APC, a tumor suppressor gene that regulates the growth of polyps.

Twenty one samples had at least one mutation that has been linked to a clinical treatment or is currently being studied in a clinical trial of targeted therapy.

For example, mutations were found in KRAS and BRAF that predict resistance to Eli Lilly's and Bristol-Myers Squibb's Erbitux (cetuximab) or Amgen's Vectibix (panitumumab), and in FBXW7 that predict anti-tubulin resistance.

Additionally, mutations were found in BRCA2 for which there are clinical trials for PARP inhibitors, in GNAS for which there are MEK- and ERK-inhibitor trials, and in PIK3CA for which there are mTOR-inhibitor trials.

The team also detected a novel gene fusion involving ALK, suggesting that ALK inhibitors such as Pfizer's Xalkori (crizotinib) may be effective.

Among the 24 non-small cell lung cancer samples, 72 percent had at least one alteration associated with a current clinical treatment or targeted therapy trial. There were mutations to KRAS, some of which point to EGFR kinase-inhibitor resistance and others that suggest eligibility for PI3K- and MEK-inhibitor trials. Mutations in BRAS suggest eligibility for BRAF-inhibitor trials, and mutations in EGFR suggest that EGFR-inhibitors such as AstraZeneca's Iressa (gefitinib) or Genentech's Tarceva (erlotinib) may be effective.

Two novel mutations were also found. A mutation at low frequency was found in JAK2, which is commonly found in myelodysplastic syndromes, but has not previously been described in solid tumors and suggests that patients with this mutation may be sensitive to JAK2 inhibitors.

Additionally, a novel gene fusion involving RET was identified in a 44-year old 'never smoker.' The team next looked for the fusion in lung cancer samples from 121 Caucasian and 405 Asian patient samples, finding it in 0.8 percent and 2 percent of the samples, respectively. Notably, the samples with the fusion did not have any known driver mutations, suggesting that the fusion may be driving the cancer.

A different RET gene fusion is frequently found in thyroid cancers, and is sensitive to RET inhibitors. A subsequent in vitro analysis found that cells with the novel fusion were also sensitive to a number of RET kinase inhibitors, suggesting that those drugs "should be tested in prospective clinical trials for therapeutic benefit in individuals with NSCLC" with the novel fusion, the authors wrote.

See the rest here:
Foundation Medicine Cancer Dx IDs Clinically Actionable Mutations, Novel Gene Fusions