HudsonAlpha Institute contributes to largest cancer genome study from NIH consortium Watch Video
HUNTSVILLE, Ala – Integrating 500 patient samples and multiple genomic technologies, The Cancer Genome Atlas Research Network has, according to a release by the National Institutes of Health, assembled the most comprehensive view of cancer genes for any cancer type to date. The analyses of data are reported in the June 30 issue of Nature.
According to Devin Absher, Ph.D., faculty investigator at the HudsonAlpha Institute for Biotechnology, and a member of the multi-organization team contributing to the analyses, key findings of this publication include the identification of a set of genes that are predictive of drug response.
“One of the benefits of doing a comprehensive analysis the way TCGA has done, is the integration of multiple types of data,” said Absher.
“The group examined how genes are expressed, whether they’ve been deleted or amplified and what point mutations might exist in those genes.”It is the integrated analyses of these factors and other data, Absher noted, that will lead to better understanding of drug response.
According to NIH, serous adenocarcinoma is the most prevalent form of ovarian cancer, accounting for about 85 percent of all ovarian cancer deaths. TCGA researchers completed whole-exome sequencing, which examines the protein-coding regions of the genome, on an unprecedented 316 tumors. They also completed other genomic characterizations on these tumors and another 173 specimens. Four subtypes of cancer were identified.
Among specific findings is the confirmation that mutations in a single gene, TP53, are present in more than 96 percent of all such cancers.
Additionally, mutations in BRCA1 and BRCA2 genes, which are associated with some forms of breast cancer, also confer increased risk for ovarian cancer. In this study, approximately 21 percent of the tumors showed mutations in these genes. Analysis of these tumors confirmed observations that patients with mutated BRCA1 and BRCA2 genes have better survival odds than patients without mutations in these genes. Investigators identified that the mechanism by which the BRCA1 and BRCA2 genes become defective also relates to survival. If either of the BRCA1 and BRCA2 genes is mutated, there is improved survival duration.
“HudsonAlpha’s role in the TCGA study of ovarian cancer,” said Absher, “was to identify amplifications and deletions in the genome.” Absher explained these instances are when genes or other regions of the genome have been lost or replicated multiple times. Those events, he added, can contribute to how tumors progress and how they respond to certain drugs.
According to Chris Gunter, Ph.D, director of research affairs at HudsonAlpha, TCGA work on ovarian cancer contributes two advances in drug treatment for patients. “First, we learned that up to 50 percent of ovarian tumors may be responsive to a type of drug called PARP inhibitors, which are already approved and ready for use. Second, HudsonAlpha’s research and data on amplifications and deletions in the genome suggested new regions to be investigated as potential drug targets in ovarian cancer overall, as well as in specific subtypes of ovarian cancer.” This, she confirmed, is a step closer to delivering individualized treatments for women grappling with the disease.
“It is exciting to be part of such a large study that integrates multiple, genomic characterization platforms,” said HudsonAlpha President Rick Myers, Ph.D. “We now know more about ovarian cancer than ever before. This voluminous data set that HudsonAlpha has helped to compile is an invaluable resource for basic and clinical researchers who are working to improve methods for diagnosing and treating ovarian cancer.”
TCGA is jointly funded and managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both part of the National Institutes of Health.
A detailed press release on the study is available from the National Institutes of Health at http://nih.gov/news/.
HudsonAlpha is part of international team releasing massive dataset
HUNTSVILLE, Ala. – The international team of the ENCODE, or Encyclopedia Of DNA Elements project, has created an overview of its ongoing large-scale efforts to interpret the human genome sequence.
The April 19 publication of “A User’s Guide to the Encyclopedia of DNA Elements (ENCODE)” in the journal PLoS Biology provides a guide for using the vast amounts of high-quality data and resources produced so far by the project. All of the data, tools to study them, and the paper itself are freely available through multiple websites accessible through encodeproject.org.
“This project requires collaboration from multiple people all over the world at the cutting edge of their fields, working in a coordinated manner to figure out the function of our human genome,” said Dr. Richard Myers, president and director of the HudsonAlpha Institute for Biotechnology and one of the 25 principal investigators of the project. “The importance extends beyond basic knowledge of who and what we are as humans and into understanding of human health and disease.”
The publication demonstrates how ENCODE data can be immediately useful in interpreting associations between single nucleotides and disease, using examples such as the c-Myc gene and cancer. Similar studies are now possible for the thousands of variants identified in genome-wide association studies, addressing mechanistic questions of susceptibility to disease.
Dr. Ewan Birney, senior scientist at the European Bioinformatics Institute and another principal investigator, commented “We knew four years ago, from our publication of ENCODE techniques on one percent of the genome, that we had an unprecedented view of how biology works on those regions. By extending our work to the entire genome, we see the immediate impact on the interpretation of noncoding variants identified in genome-wide association studies. These studies are disease-driven but have not always yielded clear next steps, and ENCODE data provide those scientists with some new paths to follow.”
Scientists with the ENCODE Project are applying up to 20 different tests in 108 commonly used cell lines to compile these important data. The current paper not only tells how to find the data, but also explains how to apply the data to interpret the human genome.
One can think of determining the human DNA sequence alone as finding a new language, but without a key to interpret the letters within. The ENCODE project adds data such as where RNA is produced from our DNA, where proteins bind to DNA, and where parts of our DNA are augmented by additional chemical markers. These proteins and chemical additions are keys to understanding how different cells within our bodies are interpreting the language of DNA.
The project is funded by the National Human Genome Research Institute, part of the National Institutes of Health.
March 8, 2011
By Monica Heger
In an example of how sequencing can be used to study not onlythe genetic underpinnings of disease but also the genetics of drug response, researchers at the HudsonAlpha Institute for Biotechnology have teamed up with clinicians at the University of Alabama, Birmingham, to perform transcriptome sequencing on 200 brain tissue samples, from patients and healthy individuals, as well as whole-exome sequencing on the genomes of 100 Parkinson’s patients enrolled in a clinical trial for the drug levodopa.
The goal of the project is two-pronged. In the RNA-seq study, the researchers hope to discover disease-causing genes. Exome sequencing of Parkinson’s patients enrolled in the clinical trial, meantime, will be used to uncover a gene or genes responsible for eliciting an adverse reaction to the drug levodopa, which, if successful, could have immediate applications in the clinic.
“If we could identify a gene, or small set of genes, which determine whether you are at risk for side effects of levodopa, it would really change our [treatment] approach,” David Standaert, a neurologist at the University of Alabama, told Clinical Sequencing News.
Levodopa, which is considered the most effective treatment for Parkinson’s, often causes the severe side effect dyskinesia, a movement disorder characterized by wild, uncontrollable movements. About half of patients given the drug develop the disorder, which can be disabling, while other patients never develop it, despite long-term use of the drug. A genetic component is believed to be involved, and if that gene or genes can be uncovered it could help guide treatment.
The researchers will use whole-exome sequencing to study 100 patients — 50 who have developed an extreme form of dyskinesia, and 50 who have shown no side effects to the drug. The patients are all enrolled in a clinical trial at the University of Alabama.
Standaert said having relevant clinical data on each patient is a key component of the project because it allows them to select patients at opposite ends of the spectrum — both those who have developed the most severe forms of dyskinesia as well as those who never develop the disorder.
“While there are collections of DNA from Parkinson’s patients, for the most part, the DNA gets disconnected from the patient and you don’t have detailed information about that patient,” Standaert said. “If we just started sequencing Parkinson’s patients randomly and tried to correlate with drug effects, that would never work.”
Identifying a genomic signature for patients with an adverse reaction to the drug could help not only those patients, but also patients who do not develop dyskinesia. Currently, clinicians are conservative in their initial dosages of levodopa and often exhaust other treatments before resorting to the drug because there is no way to tell how a patient will react. But, said Standaert, if the clinician could identify which patients were at low risk of developing the disorder, they could be started on the drug earlier in treatment and potentially at higher dosages.
“Right now, we’re often very conservative and don’t give [levodopa] out, but there are probably many patients who could take it safely,” he said. Mark Hallett, chief of the medical neurology branch at the National Institute of Neurological Disorders and Stroke said that understanding the genetic basis of levodopa response could have immediate impacts on treatment.
“Where dyskinesias come from is not at all clear,” he said. “If there is a genetic difference that could be identified, that would be very helpful.”
For instance, he said he recently saw a patient who is starting to show symptoms of Parkinson’s. The patient was reluctant to start levodopa treatment right away because of concerns about the side effects. However, if there were a genetic test that could determine the patient’s risk of developing dyskinesia, that would likely influence treatment decision, said Hallett.
“It could influence how soon you start levodopa, or whether to use an alternative medication. It might influence therapy from the get go,” he said. Standaert is in the midst of recruiting patients and gaining regulatory approval for the study. He said that patients will have to sign a consent form indicating that they understand that because exome sequencing is not proven to have value in clinical care, the results will not be returned. “It’s a very slippery slope when you start to give patients information that may or may not be correct,” Standaert said. “That kind of information can be misleading in clinical care.”
He added, however, that he has been working with the institutional review board to evaluate how best to deal with the exome sequencing results, particularly since there is very little precedent on how to incorporate sequencing into clinical trials.
Rick Myers’ team at the HudsonAlpha Institute will do the exome sequencing, which Myers said he expects will begin toward the middle of the year. Myers’ team will also perform the transcriptome sequencing of the 200 brain tissue samples, which are being provided by neurologist John Trojanowski at the University of Pennsylvania. Myers said that most of the sequencing for both projects will be done on the Illumina HiSeq instrument, but added that they might do some microRNA sequencing on Life Technologies’ SOLiD. Aside from the HiSeq and SOLiD, the institute also operates Roche’s 454 GS FLX platform and Ion Torrent’s PGM.
Myers said his team has already begun the transcriptome sequencing portion of the project, the goal of which is to identify disease genes. While Parkinson’s is believed to have genetic roots, so far only a handful of genes have been linked to the disease, and they collectively account for only about 10 percent of all cases, said Standaert.
Ideally, Myers said, the team would discover biomarkers that would allow for early diagnosis of the disease, as well as a way to predict what form the disease would take in terms of age of onset, severity, and drug response. In addition, he said, those genes could then serve not only as diagnostic tools, but also potentially as new drug targets.
The project is funded by a $500,000 donation from philanthropist John Jurenko, and Myers said that depending on costs, it could be expanded to include methylome sequencing, additional samples, or even whole-genome sequencing. The sequencing is expected to be completed by the end of 2012.
While it is still early days for combining sequencing technology with clinical trials, the project is not the first of its kind. Washington University researchers are sequencing breast cancer patients enrolled in an aromatase inhibitor drug trial, for instance (IS 8/10/2010), and both Standaert and Myers said they expect to see more trials like this in the future.
“We’re already seeing dozens of examples of this,” Myers said. “And, I think sequencing is going to be applied clinically more and more.”
November 22, 2010
Newly announced HudsonAlpha resident associate company Kailos Genetics and Dr. K-T Varley of Myers Lab are featured in a Fall 2010 Technology Alabama article. The full story is attached as a PDF.
October 15, 2009
A gene has been associated with human kidney aging, according to researchers from Stanford University, the National Institute on Aging, the MedStar Research Institute, and the HudsonAlpha Institute for Biotechnology. In work published on October 16 in the open-access journal PLoS Genetics, the investigators, including HudsonAlpha Faculty Investigators Rick Myers and Devin Absher, claim that their approach can be applied to any phenotype of interest to help find other genetic associations.
Kidneys age at different rates, such that some people show little or no effects of kidney aging whereas others show rapid functional decline. Determining genetic factors associated with different rates of kidney aging contributes to the understanding of molecular mechanisms underlying the human aging process. Although family studies have shown that genes play a role in longevity, it has proven difficult to identify the specific genetic variants involved, until now.
Because data from both populations were combined in the kidney aging association analysis, the researchers stress that this finding needs to be replicated in additional populations. As more aging genes are discovered and confirmed, the particular genetic variants belonging to a person could one day be combined to better predict the aging trajectory of the kidney.
Click here to read the full entry in PLoS Genetics.
September 1, 2009
It is probably a safe bet that genomics would be a slightly different place had Richard Myers pursued his original path. Myers — now president and director of the Hudson-Alpha Institute for Biotechnology in Huntsville, Ala. — began his academic career as a sociology major at the University of Alabama in the mid-1970s. But halfway through, he ended up in a chemistry class that captured his interest and caused him to drop the softer science cold. And it’s a good thing, too, because Myers went on to play a major role in the Human Genome Project, among many other large-scale collaborations. From 1993 until 2008, Myers was a professor in the department of genetics at Stanford University School of Medicine, where he also directed the Stanford Human Genome Center. In fact, Myers and his genome center contributed roughly 11 percent of the human sequence — chromosomes 5, 16, and 19.
But in 2008, with much ado that included a glowing endorsement from Alabama Governor Bob Riley, Myers officially made the move to HudsonAlpha. In addition to being handed the steering wheel of a new institute, this was a homecoming of sorts for the Tuscaloosa native.
Myers’ lab continues to work with the Joint Genome Institute and has sequenced the genomes of more than 40 organisms related to bioenergy, agricultural, and environmental problems. His lab is also part of the Pritzker Neuropsychiatric Disorders Research Consortium, which studies mood disorders with gene expression studies, and the Cancer Genome Atlas project. And in case those commitments don’t keep him busy enough, Myers also finds time to serve on the HapMap Advisory Committee and the Review Group for Large-Scale DNA Sequencing Centers of the National Human Genome Research Institute, as well as on the Biology and Biotechnology Program Advisory Committee for the US Department of Energy.
A family lab
Myers prides himself on maintaining a close-knit family in his lab that is as big as it is diverse. Back in the 1990s, the Myers lab was made up of more than 50 people with a wide array of specialties and at different stages of their career. “I’ve had a fairly good-sized lab for the last 20 years because of the genomics aspects to it — and that’s been a combination of students and postdocs, but also what I call senior scientists and compute technicians and computer scientists,” Myers says. “So I train at the level of people getting the PhDs and postdocs, but also these big projects that work collaboratively with lots of different groups.”
Myers admits that he was a workhorse during his early career, but he doesn’t crack the whip on his own students — they are the only ones who can decide how hard to work. “I have always worked really hard myself. In the labs I worked in before, people worked ridiculously long hours, but I never push people to work specific hours,” he says. “I just think people should work the way that fits their careers, and people who worked hard and had the capability were going to do well and people who didn’t may not do as well.”
Collegiality is also high on his list of requisite qualities for potential applicants. “Just the thought of having someone in your group who is going to be greedy or disruptive or selfish all the time would not go over well, and would make the lab an unpleasant place to be, so that was always important to me,” Myers says. “The idea of pitting one student against another, I saw a little bit of that in some of the places I’ve been earlier and thought it was pretty repulsive, so I really worked hard not to do that.”
Myers says that handling whatever personalities come his way in the lab is something he learned over time, and it was not always easy — especially when he first started and had postdocs who were almost the same age as he was. But like any good leader, Myers has developed some tricks to deal with the myriad personality types that step through the door of his oftentimes crowded lab. “I’m a pretty social person and have reasonably good instincts and decent people skills, but I was all over the place — I had people who were wonderful and people who were incredibly disruptive who the lab wanted to throw out the window, and I had to deal with all of that,” he says. “By now I’ve learned some rules I try to follow. The most important thing is to insist that people treat each other well because you’re in a tight environment and often the lab spaces are quite crowded. … One of the things that I try to do is to not make it feel tense.”
When it comes to preparing his students to go out into the world, Myers says confidence is key, but that some students don’t have the self-confidence they should. “I remember one student telling me he wasn’t good enough to be in academia, whatever that meant, and he’s now a professor at a prominent university [and] doing very well,” Myers says. “So part of that is trying to overcome this perception that life is way too hard in academia doing research. There’s so many different venues to do it, and yes there are some fields that are much tighter than others, and the field we’re in is still in quite a large demand and [that] may not last forever.”
In addition to having self-confidence, Myers really wants his students to be good “scientific citizens” with an appreciation for the opportunities public funding allows them, as well as having integrity and strong communication skills. “I very much encourage my students and postdocs to feel that they owe the world something because we’re getting to do this,” he says. “And I certainly want them to be good experimentalists, good at analyzing their data and being straight and honest about that, and then also I really try and encourage people to enjoy it. There is a lot of fun and joy in making a discovery and you don’t have to be a superhero to make a real contribution.”
Over the last 20 years of having a large lab, Myers’ tutelage has been critical to many scientists learning the ropes. Here are some of the names you might recognize.
Shelley Force Aldred
During her graduate years with Myers, Aldred studied how stretches of DNA regulate when and where a gene is used. Aldred co-founded SwitchGear Genomics with Myers and now serves as the company’s president and chief operating officer.
Li cut his teeth on human genetics during his postdoc position with Myers, in which he learned the value of large-scale association studies. He is now an assistant professor at the University of Michigan, where he takes part in several collaborative studies on bipolar disorder, cardiovascular disease, and cancer.
Noonan obtained his PhD under Myers’ guidance. He is now an assistant professor at Yale University, where he uses computational and experimental approaches to study the genetic mechanisms that underlie the phenotypic divergence of humans from other primates.
Currently a senior staff scientist at Lawrence Berkeley National Laboratory, Pennacchio was a graduate student under Myers when he helped to uncover the genetic cause for a rare form of epilepsy.
Tabor first came to know Myers while a graduate student studying epidemiology and genetics. After completing her degree, she became a senior scientist in his lab. Tabor is now an assistant professor at the University of Washington School of Medicine and the Treuman Katz Center for Pediatric Bioethics.
After finishing his PhD with Myers, Trinklein went on to manage the Stanford part of the ENCODE project before co-founding SwitchGear Genomics. Trinklein is currently the chief executive officer of SwitchGear, where he manages all technology development in the area of regulatory network/pathway analysis.
Myers’ work highlighted
The local chapter of the American Cancer Society will once again honor cancer survivors, as well as those who have been lost to the disease during the ACS Summer Lights Celebration on August 22.
An addition to this year’s program is a salute to cancer research. “This year we have the opportunity to recognize the research of Dr. Rick Myers,” said Jo Ann Henderson, executive director of the chapter. “Dr. Myers and the research conducted by his team will lead the way to advances in understanding the complexities of the human genome that will ultimately lead to advances in cancer treatments. We look forward to celebrating and recognizing his research efforts.” Honorees also include two local cancer survivors: author Homer Hickam and Huntsville native Katie Sanders.
The celebration will be held at the Von Braun Center.