Category Archives: Genetic Medicine

Public release date: 20-Jun-2012 [ | E-mail | Share ]

Contact: Nicole Davis ndavis@broadinstitute.org 617-714-7152 Broad Institute of MIT and Harvard

Breast cancer is not a single disease, but a collection of diseases with dozens of different mutations that crop up with varying frequency across different breast cancer subtypes. Deeper exploration of the genetic changes that drive breast cancer is revealing new complexity in the leading cause of cancer death in women worldwide.

In one of the largest breast cancer sequencing efforts to date, scientists from the Broad Institute, the National Institute of Genomic Medicine in Mexico City, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute have discovered surprising alterations in genes that were not previously associated with breast cancer. They report their results in the June 21 issue of Nature, which is publishing a series of papers characterizing the genomic landscape of breast cancer.

One of the team's new findings, a recurrent fusion of the genes MAGI3 and AKT3 in what is known as a translocation event, was observed in tumors from a rare but aggressive form of breast cancer known as triple-negative breast cancer. This cancer does not respond to conventional hormone therapy because its tumors lack three receptors that fuel most breast cancers: estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (known as HER2). But the biological pathway that is affected by the MAGI3-AKT3 reshuffling is already the target of experimental drugs.

The other new alteration reported by the team occurred in two transcription factor genes. Recurrent mutations were detected in the gene CBFB and deletions of its partner RUNX1. Cancer-causing rearrangements of these two genes are common in blood cancers, such as acute myeloid leukemia, but their discovery in breast cancer marks the first time they have been seen in a solid cancer.

"These genes wouldn't top the list of genes you think would be mutated in breast cancer," said Alfredo Hidalgo Miranda, co-senior author of the paper and head of the cancer genomics laboratory at the National Institute of Genomic Medicine, known by its Spanish acronym INMEGEN. "That's exactly the point of doing this type of analysis. It gives you the opportunity to find those genes that you never thought would be involved in the breast cancer process."

The scientists studied two kinds of samples. They sequenced the whole exomes - the tiny fraction of the genome that encodes proteins of 103 breast cancer tumors and DNA from normal tissue from patients in Mexico and Vietnam. They also sequenced the entire genomes of 22 breast cancer tumors and matched normal tissue.

Their analysis confirmed the presence of previously known mutations, but it also turned up the unsuspected alterations.

"One of the lessons here is the real diversity of mutations in breast cancer. I think it's clear there are going to be roughly 50 or so different mutated genes in breast cancer," said Matthew Meyerson, co-senior author of the paper, Broad senior associate member, and professor of pathology at Dana-Farber Cancer Institute and Harvard Medical School. "There's a big diversity of driver genes in cancer. We don't understand what all of them are, but larger data sets will enable us to identify them."

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Breast cancer's many drivers

Public release date: 19-Jun-2012 [ | E-mail | Share ]

Contact: Nicole White nicole.white@cshs.org 310-423-5215 Cedars-Sinai Medical Center

LOS ANGELES (June 19, 2012) Cedars-Sinai's Regenerative Medicine Institute has pioneered research on how motor-neuron cell-death occurs in patients with spinal muscular atrophy, offering an important clue in identifying potential medicines to treat this leading genetic cause of death in infants and toddlers.

The study, published in the June 19 online issue of PLoS ONE, extends the institute's work to employ pluripotent stem cells to find a pharmaceutical treatment for spinal muscular atrophy or SMA, a genetic neuromuscular disease characterized by muscle atrophy and weakness.

"With this new understanding of how motor neurons die in spinal muscular atrophy patients, we are an important step closer to identifying drugs that may reverse or prevent that process," said Clive Svendsen, PhD, director of the Cedars-Sinai Regenerative Medicine Institute.

Svendsen and his team have investigated this disease for some time now. In 2009, Nature published a study by Svendsen and his colleagues detailing how skin cells taken from a patient with the disorder were used to generate neurons of the same genetic makeup and characteristics of those affected in the disorder; this created a "disease-in-a-dish" that could serve as a model for discovering new drugs.

As the disease is unique to humans, previous methods to employ this approach had been unreliable in predicting how it occurs in humans. In the research published in PLoS ONE, to the team reproduced this model with skin cells from multiple patients, taking them back in time to a pluripotent stem cell state (iPS cells), and then driving them forward to study the diseased patient-specific motor neurons.

Children born with this disorder have a genetic mutation that doesn't allow their motor neurons to manufacture a critical protein necessary for them to survive. The study found these cells die through apoptosis the same form of cell death that occurs when the body eliminates old, unnecessary as well as unhealthy cells. As motor neuron cell death progresses, children with the disease experience increasing paralysis and eventually death. There is no effective treatment now for this disease. An estimated one in 35 to one in 60 people are carriers and about in 100,000 newborns have the condition.

"Now we are taking these motor neurons (from multiple children with the disease and in their pluripotent state) and screening compounds that can rescue these cells and create the protein necessary for them to survive," said Dhruv Sareen, director of Cedars-Sinai's Induced Pluripotent Stem Cell Core Facility and a primary author on the study. "This study is an important stepping stone to guide us toward the right kinds of compounds that we hope will be effective in the model and then be reproduced in clinical trials."

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Cedars-Sinai researchers, with stem cells, advance understanding of spinal muscular atrophy

When helping patients to quit smoking, physicians need to understand that an individuals ability to kick the habit is related, in part, to his or her genetic makeup, said psychiatrist Li-Shiun Chen, MD, MPH, ScD.

Adults with genetic variants that put them at high risk of heavy smoking and nicotine dependence smoked longer than those without such genetic markers. These adults also were less likely to quit without the help of medication, such as bupropion, according to a study published online May 30 in The American Journal of Psychiatry.

Its great for physicians to understand that not everyone can quit smoking easily on their own, said Dr. Chen, lead author of the study and assistant professor of psychiatry at Washington University School of Medicine in St. Louis. The genetic testing is not all worked out yet, but in the future, we are hoping to tailor appropriate [smoking cessation] treatment for our patients using their genetic makeup and other risk factors.

A persons risk of heavy smoking and dependence on nicotine are associated with variants in a cluster of nicotine receptor genes, CHRNA5-CHRNA3-CHRNB4, according to the study.

Researchers examined data on 5,216 smokers who were 45 to 64 years old when they joined the Atherosclerosis Risk in Communities study in 1987.

They also looked at data on 1,073 adults 18 and older who joined a three-year smoking cessation study at the University of Wisconsin Center for Tobacco Research and Intervention between January 2005 and June 2007.

Researchers found the median age for quitting smoking was 57 among those with the high-risk form of the gene cluster, compared with 55 for other participants (ncbi.nlm.nih.gov/pubmed/22648373/).

Genetics will enable us to help patients quit earlier, and that will decrease a lot of smoking-related disorders, Dr. Chen said.

People with high-risk genetic markers were more likely to fail in their attempts to quit smoking when treated with placebo, compared with those with low-risk genes, the study said. But medications used for nicotine cessation increased the likelihood of kicking the habit in the high-risk group. People in this group were three times as likely to quit smoking with the help of pharmacologic treatments than were people with low-risk genetic markers.

The findings indicate that individuals with low-risk genes likely will be able to quit successfully without the help of smoking-cessation medications, Dr. Chen said.

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Smokers’ ability to quit linked to genetic makeup

CARLSBAD, Calif., June 19, 2012 /PRNewswire/ -- Life Technologies Corporation (LIFE) today announced it has partnered with The Hospital for Sick Children (SickKids) to advance pediatric genomic research on the Ion Proton Sequencer. Under the agreement, the semiconductor-based platform will be the primary instrument on which multiple clinical research samples will be mapped daily on four sequencers in the hospital's newly launched Centre for Genetic Medicine.

SickKids and Life Technologies will collaborate on developing sequencing workflows and protocols for the Ion Proton System that are tailored for studies of interest to researchers in the Centre. The first collaborative project will focus on sequencing clinical research samples to better understand the genetics behind autism, with a long-term goal to sequence up to 10,000 genomes per year to study various diseases in children.

"The perfect storm of unparalleled advances in genome sequencing technology and information science, and a captivated hospital striving for new ways to move forward in medical treatment, bring us to this important day," says the new Centre's Co-Director, Dr. Stephen Scherer, who also leads The Centre for Applied Genomics at SickKids and the University of Toronto's McLaughlin Centre. "We are very excited to work with Life Technologies to enhance our sequencing capabilities, such that 'genomic surveillance' may soon become the first line of investigation in all clinical research studies ongoing at our institution."

"Since the first published draft sequence of the human genome, our knowledge in genetics has exponentially increased," says Dr. Ronald Cohn, Co-Director of the SickKids Centre for Genetic Medicine. "With the help of this new technology, we will be able to further deepen our understanding of the genetic basis of human disease and translate this directly into daily clinical practice. We have finally reached a point, where individualized medicine is not just a theoretical concept, but will become an integral part of clinical care and management."

The Ion Proton Sequencer is designed to sequence an entire human genome in a day for $1,000. Unlike traditional next generation systems, it relies on semiconductor chips to map human exomes and genomes, making it much faster and less expensive to analyze DNA at unprecedented throughput levels and generate accurate sequencing data.

The Ion Proton Systemis based on the same proven technology as its predecessor, the Ion Personal Genome Machine (PGM), which is designed for sequencing small genomes or sets of genes. Combined with Life Technologies' AmpliSeq targeted sequencing technology, researchers can sequence panels of genes associated with disease on the PGM or exomes and genomes on the Ion Proton Sequencer in just a few hours.

"SickKids has a rich history of being at the forefront of pediatric medicine and we are pleased that its leaders have chosen the Ion Proton Sequencer as the Centre's primary technology to push the boundaries of genomics," said Mark Stevenson, President and Chief Operating Officer of Life Technologies. "Ion semiconductor technology's speed, simplicity and scalability are democratizing sequencing, and it will now be applied in disease research to benefit children."

The above mentioned technology is for research use only and not intended for human diagnostic or therapeutic use.

About Life Technologies Life Technologies Corporation (LIFE) is a global biotechnology company with customers in more than 160 countries using its innovative solutions to solve some of today's most difficult scientific challenges. Quality and innovation are accessible to every lab with its reliable and easy-to-use solutions spanning the biological spectrum with more than 50,000 products for translational research, molecular medicine and diagnostics, stem cell-based therapies, forensics, food safety and animal health. Its systems, reagents and consumables represent some of the most cited brands in scientific research including: Ion Torrent, Applied Biosystems, Invitrogen, GIBCO, Ambion, Molecular Probes, Novex, and TaqMan. Life Technologies employs approximately 10,400 people and upholds its ongoing commitment to innovation with more than 4,000 patents and exclusive licenses. LIFE had sales of $3.7 billion in 2011. Visit us at our website: http://www.lifetechnologies.com.

Life Technologies' Safe Harbor StatementThis press release includes forward-looking statements about our anticipated results that involve risks and uncertainties. Some of the information contained in this press release, including, but not limited to, statements as to industry trends and Life Technologies' plans, objectives, expectations and strategy for its business, contains forward-looking statements that are subject to risks and uncertainties that could cause actual results or events to differ materially from those expressed or implied by such forward-looking statements. Any statements that are not statements of historical fact are forward-looking statements. When used, the words "believe," "plan," "intend," "anticipate," "target," "estimate," "expect" and the like, and/or future tense or conditional constructions ("will," "may," "could," "should," etc.), or similar expressions, identify certain of these forward-looking statements. Important factors which could cause actual results to differ materially from those in the forward-looking statements are detailed in filings made byLife Technologies with the Securities and Exchange Commission.Life Technologies undertakes no obligation to update or revise any such forward-looking statements to reflect subsequent events or circumstances.

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The Hospital for Sick Children in Toronto Adopts Life Technologies' Ion Proton™ Sequencer to Launch New Centre for ...

Psychiatrists often try two or more medications in a patient suffering with major depression before settling on the one that seems to work best for that individual. Sometimes, after several are tried and abandoned, two (or even three) are used in combination.

Medication selection is part of the art of psychiatry, but, now, testing is available that promises to make it more of a science. A company called AssureRx Health now offers what it calls GeneSightRxpharmacogenomic laboratory testing that helps identify which antidepressants are a good match for a persons genetic makeup, and which are not so good a match.

Sometimes, the testing reveals why three or four antidepressants havent worked for a patient, while pointing in the direction of one that might.

This is extremely good news, because psychiatrists have several different kinds of antidepressants to choose fromsome which increase the activity of the brain chemical messenger serotonin, some which increase the activity of the brain chemical messenger norepinephrine and some which increase both. And they do so by varying mechanisms, requiring the activity of different enzymes.

The technology behind GeneSightRx actually determines which genetic variantsin terms of the enzymes that are activated by antidepressantsa person possesses.

Different antidepressants affect the enzymes very differently. Hence, the testing can literally predict with some accuracy which antidepressants are likely to work in a particular person, and which are likely to cause the fewest side effects.

Recent studies have revealed that antidepressants dont work much better than placebo medications (sugar pills) for many patients. But those studies werent conducted by first selecting patients who are more likely (as determined by GeneSightRx) to respond to the particular medicine being studied.

Its very possible that patients given medications suggested by such testing would do far better than those given placebosbecause they arent being lumped together and given one medicine, regardless of their individual genetic makeup.

Moreover, since many patients discontinue their antidepressants due to side effects like sexual dysfunction and sleeplessness, choosing a medication that is metabolically and genetically less likely to cause these and other side effects makes good sense.

GeneSightRx also predicts which ADHD medications, antipsychotics and pain medications patients are likely to respond to and from which they are likely to experience fewer side effects.

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Genetic testing to choose the right antidepressant

Alexandra Stern is a University of Michigan historian of medicine and expert on eugenics who lectured at the University of Houston this spring on disability rights. The author of the forthcoming "Telling Genes: The Story of Genetic Counseling in America," she spoke with Chronicle medical reporter Todd Ackerman after the lecture about the limitations of genetic medicine, whether to take advantage of for-profit company genetic tests and how eugenics didn't die out with the Holocaust.

Q: In the history of medicine, how is the early 21st century likely to be remembered? Is this the genetic era, or is that still to come?

A: The genetic era has begun, but the big question is what we do with the information we now have to help people - to what extent will it lead to cures and more effective therapies? History shows the expectations and promise of a new era's technology are often much greater than what ends up being delivered.

Q: So you think we're likely to be disappointed?

A: Unfortunately, yes. We're a society in which people are interested in their DNA, how genetics affects them, but also want quick solutions, primed by the great progress we've seen in medicine from, for instance, vaccines and antibiotics. But those magic bullets don't translate well to genetic medicine. I don't want to come across as suggesting there won't be great outcomes, but the idea that we'll simply be able to decode the genome, tailor medicines to a particular person based on their genome and cure chronic disease I think there will be a lot of unmet expectations along those lines.

Q: How much are people receiving genetic diagnoses at this point?

A: Genetic tests or diagnoses are being offered in more and more areas of clinical medicine - from neurology to cardiology to oncology. But you're probably talking about those for-profit companies doing genomic testing that return a whole scorecard of probabilities of developing certain conditions.

I think people are increasingly seeking those out and that the problem is that what they get back is unfiltered. People not only need help deciphering their information, they also need help, from a genetic counselor, dealing with the psychological decision-making quandaries they face as a result of genetic testing, how to cope if you have a higher-than-average probability of developing, say, Alzheimer's.

Q: Has enough attention been paid to ethical questions raised by the coming genetic era?

A: It depends on whom you're talking about. Discussions tend to be very fragmented: bioethicists amongst themselves; scientists amongst themselves; disability rights people amongst themselves. But as a society are we having broad-based discussions about the ethical implications, what the priorities should be and what the changes mean for people with disabilities? I don't think so.

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Eugenics shadow still 'looms large,' historian says