Category Archives: Genetic Medicine

A team of Stanford researchers has unveiled the most detailed biological profile of a human being done so far: a peek at one man's genetic foundation, along with snapshots, taken dozens of times over the course of a year, of the millions of proteins and other molecules that are in constant flux in his body.

In a stroke of shocking good luck - for the scientists, if not necessarily the patient - the profile subject developed Type 2 diabetes during the study, allowing researchers to follow in real time the molecular changes that took place as the illness progressed.

It also allowed the subject, Stanford geneticist Michael Snyder, to catch his diabetes early and stop it, most likely months or even years before he would have been diagnosed without the genetic profiling.

"This is the first time someone's actually analyzed the genome of a healthy person, predicted disease risk, and then by following him, actually saw a disease develop," said Snyder, who in addition to being the subject of the study was the senior author.

Snyder's profile and an analysis of the results were published today in the journal Cell. Snyder, chairman of the genetics department at Stanford, is not named in the published study because of privacy rules, but he volunteered to identify himself.

The research provides some of the first proof that detailed genetic profiling - beyond just DNA sequencing - could be used someday not just to predict an individual's chances of developing disease, but also to identify the smallest molecular changes that show when a person starts to become ill, said experts in personalized medicine.

The first human genome - a map of all of the DNA in a human cell - was announced in 2000. Seven or eight years later geneticists began mapping the genomes of specific individuals. Such personal genomic sequencing is expected to become widely available this year, at a cost of several thousand dollars.

Using genetic information to help diagnose and treat patients is still a very new field, although it's growing rapidly. Certain key genes have been found to greatly increase the risk of breast cancer, for example, or the deadly Huntington's disease, and doctors will regularly test for those genes when someone is diagnosed with an illness or when a close family member is known to have a disease.

But for most people, DNA sequencing and other biological profiling isn't yet useful - subjects would end up with a lot of unwieldy information that is mostly beyond modern scientific understanding or far too expensive to analyze.

"What they did (at Stanford) is much more interesting from a scientific basis than a practical basis," said Dr. David Witt, a medical geneticist at Kaiser San Jose. "And that gets to the heart of personalized medicine: It's not ready for prime time."

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Stanford man's genetic profile yields surprises

Editor's Choice Academic Journal Main Category: Lymphoma / Leukemia / Myeloma Also Included In: Cancer / Oncology;Genetics Article Date: 16 Mar 2012 - 9:00 PDT

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Ross Levine, M.D., lead author of the study, member of Memorial Sloan-Kettering's Human Oncology Pathogenesis Program, and a medical oncologist on the Leukemia Service at Memorial Sloan-Kettering, said:

We also want to use existing therapies more intelligently. It helps a great deal to know which subset of patients will actually benefit from intensive therapies, such as a higher dose of chemotherapy or a bone marrow transplant."

Currently, there are just a few known genetic biomarkers that clinicians rely on in order to predict outcome in individuals suffering with leukemia. Although these biomarkers provide helpful information for some patients with AML, for the majority it is hard to predict the chance for a cure.

The researchers used a method that incorporated information from a set of genes. This allowed them to categorize almost two-thirds of patients into clearly defined prognostic groups.

Dr. Levine, explained:

"Our goal was not to ask whether a certain gene or two raised or lowered risk, but to determine whether a combination of characteristics from a set of genes made it possible to precisely stratify patients according to risk."

The team examined blood or bone marrow samples from 502 individuals with AML who took part in a clinical trial conducted by Martin S. Tallman, M.D., Chief of Memorial Sloan-Kettering's Leukemia Service. The aim of the trial was to determine whether increasing the standard dose of chemotherapy would improve survival for individuals with AML under the age of 60.

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Leukemia Patients' Outcomes Predicted With Genetic Profiling

PHILADELPHIA A growing body of evidence underscores the importance of human gut bacteria in modulating human health, metabolism, and disease. Yet bacteria are only part of the story. Viruses that infect those bacteria also shape who we are. Frederic D. Bushman, PhD, professor of Microbiology at the Perelman School of Medicine at the University of Pennsylvania, led a study published this month in the Proceedings of the National Academy of Sciences that sequenced the DNA of viruses -- the virome -- present in the gut of healthy people.

Nearly 48 billion bases of DNA, the genetic building blocks, were collected in the stools of 12 individuals. The researchers then assembled the blocks like puzzle pieces to recreate whole virus genomes. Hundreds to thousands of likely distinct viruses were assembled per individual, of which all but one type were bacteriophages viruses that infect bacteria -- which the team expected. The other was a human pathogen, a human papillomavirus found in a single individual. Bacteriophages are responsible for the toxic effects of many bacteria, but their role in the human microbiome has only recently started to be studied.

To assess variability in the viral populations among the 12 individuals studied, Bushman's team, led by graduate student Samuel Minot, looked for stretches of bases that varied the most.

Their survey identified 51 hypervariable regions among the 12 people studied, which, to the team's surprise, were associated with reverse transcriptase genes. Reverse transcriptase enzymes, more commonly associated with replication of retroviruses such as HIV, copy RNA into DNA. Of the 51 regions, 29 bore sequence and structural similarity to one well-studied reverse transcriptase, a hypervariable region in the Bordetella bacteriophage BPP-1. Bordetella is the microbe that causes kennel cough in dogs.

BPP-1 uses reverse transcriptase and an error-prone copying mechanism to modify a protein to aid in entering and reproducing in a wide array of viral targets. Bushman and colleagues speculate that the newly discovered hypervariable regions could serve a similar function in the human virome, and microbiome, by extension.

"It appears there's natural selective pressure for rapid variation for these classes of bacteriophages, which implies there's a corresponding rapidly changing environmental factor that the phage must be able to quickly adapt to," says Minot. Possible reasons for change, say the authors, include evading the immune system and keeping abreast of ever-evolving bacterial hosts a kind of mutation-based host-pathogen arms race. Whatever the case, Minot says, such variability may be helping to drive evolution of the gut microbiome: "The substrate of evolution is mutation."

Evolutionary analysis of the 185 reverse transcriptases discovered in this study population suggests that a large fraction of these enzymes are primarily involved in generating diversity. Now, Minot says, the challenge is to determine the function of the newly discovered hypervariable regions, and understand how their variability changes over time and in relationship to disease.

"This method opens a whole new world of 'diversity-generating' biology to discover what these clearly important systems are actually doing," he says.

In addition to Bushman and Minot, co-authors are Stephanie Grunberg (Department of Microbiology); Gary Wu (Division of Gastroenterology); and James Lewis (Department of Biostatistics and Epidemiology), all from Penn.

The research was supported by grants from the National Institutes of Health, Pennsylvania Department of Health, and the Crohn's and Colitis Foundation of America.

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Genetic Variation in Human Gut Viruses Could be Raw Material for Inner Evolution, Perelman School of Medicine Study ...

Newswise The diagnosis of myelodysplastic syndrome, a blood cancer, often causes confusion. While some patients can be treated with repeated blood transfusions, others require chemotherapy, leaving some uncertainty about whether the syndromes actually are cancer.

Now, using the latest DNA sequencing technology, scientists at the Washington University School of Medicine in St. Louis have shown that the blood disease is an early form of cancer with characteristics that are very similar to the fatal leukemia to which it often progresses. And by mapping the genetic evolution of cancer cells in seven patients with myelodysplastic syndromes who later died of leukemia, they have found clues to suggest that targeted cancer drugs should be aimed at mutations that develop early in the disease.

The research, by a large team of Washington University researchers at the Siteman Cancer Center, appears online March 14 in the New England Journal of Medicine.

The scientists sequenced all the DNA the genome of tumor cells from the patients over time. While some cancer cells in each patient acquired new mutations as they evolved, they always retained the original cluster of mutations that made the cells cancerous in the first place.

This discovery, which must be confirmed in larger studies, suggests that drugs targeted to cancer mutations might be more effective if they are directed toward genetic changes in the original cluster of cancer cells called the founding clone. Drugs that target mutations found exclusively in later-evolving cancer cells may kill those cells but likely wouldnt damage founding clones that do not carry the later mutations.

Its probably not enough to know that a particular mutation exists in cancer cells, says senior author Timothy Graubert, MD, associate professor of medicine at the School of Medicine who also treats patients at Barnes-Jewish Hospital. We likely will need to dig deeper to find out whether a mutation is in the founding clone that initiated the cancer or in a later-evolving clone.

In other words, think of this cancer as a tree, Graubert says.

To kill a tree, you have to pull out the roots, he says. If you only cut off a limb, it will just grow back. Were saying that to be effective, targeted cancer drugs probably need to attack mutations at the root of this disease.

About 28,000 Americans are diagnosed with myelodysplastic syndromes each year, most over age 60. They occur when blood cells produced in the bone marrow dont fully develop and immature cells crowd out healthy ones. In about one-third of patients, the disease progresses to a fatal form of leukemia.

As part of the new research, Graubert and his colleagues teamed with researchers at Washington Universitys Genome Institute who sequenced the genomes of cancer cells after the patients developed acute myeloid leukemia. Then, they determined whether the mutations they found were present when the same patients were first diagnosed with myelodysplastic syndromes.

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Scientists Map Genetic Evolution of Leukemia

ScienceDaily (Mar. 15, 2012) A collaborative discovery involving Kansas State University researchers may improve animal health and save the U.S. pork industry millions of dollars each year.

Raymond "Bob" Rowland, a virologist and professor of diagnostic medicine and pathobiology, was part of the collaborative effort that discovered a genetic marker that identifies pigs with reduced susceptibility to porcine reproductive and respiratory syndrome, or PRRS. This virus costs the U.S. pork industry more than $600 million each year.

"This discovery is what you call a first-first," Rowland said. "This discovery is the first of its kind for PRRS but also for any large food animal infectious disease. I have worked in the field for 20 years and this is one of the biggest advances I have seen."

Rowland and researchers Jack Dekkers from Iowa State University and Joan Lunney from the Agricultural Research Service discovered a genetic marker called a quantitative trait locus, or QTL, which is associated with porcine reproductive and respiratory syndrome virus susceptibility. This discovery is a first step in controlling and eliminating the virus.

The research recently appeared in the Journal of Animal Science. The project's beginning and future center around Kansas State University, Rowland said.

It begins at the university because Rowland is involved with an organization called the PRRS Host Genetics Consortium, or PHGC, which initiated and provided more than $5 million for the research. Rowland is co-director of the consortium, which is a collaboration among the United States Department of Agriculture, the National Pork Board and Genome Canada as well as universities and industry members. Rowland is also director of the USDA-funded PRRS Coordinated Agriculture Project, known as PRRS CAP.

"The PRRS Host Genetics Consortium takes fundamental science and turns it into utility," Rowland said.

Kansas State University's new Large Animal Research Center is the site of much of the project's experimental work. The researchers obtain multiple measurements -- including growth, weight gain, performance and virus measurements -- over time. They have collected samples from more than 2,000 pigs since they began the study in 2007, for a total of more than 100,000 samples that are stored or distributed to the consortium's collaborators.

The university shipped samples to the Agricultural Research Service for genomic DNA preparations to identify differences among more than 60,000 genes. The data was transferred to Iowa State University for genetic analysis that led to the discovery of the QTL.

The collaborators at Iowa State University created a common database so that all the data collected during the project can be accessed at multiple locations by researchers and the breeding industry for the next several decades.

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Animal health breakthrough: Research uncovers genetic marker that could help control, eliminate PRRS virus

Newswise NEW YORK, MARCH 14, 2012 Researchers have identified a set of genetic abnormalities in patients with acute myelogenous leukemia (AML) that doctors can use to more accurately predict patients prognoses and select treatments that are most likely to benefit them. The study, led by investigators at Memorial Sloan-Kettering Cancer Center, will be published in the March 22 issue of the New England Journal of Medicine.

Our study shows that genetic profiling makes it possible to more precisely categorize which patients are most likely to have their leukemia return after treatment, says the studys lead author Ross Levine, MD, a member of Memorial Sloan-Ketterings Human Oncology Pathogenesis Program. We also want to use existing therapies more intelligently. It helps a great deal to know which subset of patients will actually benefit from intensive therapies, such as a higher dose of chemotherapy or a bone marrow transplant, adds Dr. Levine, who is also a medical oncologist on the Leukemia Service at Memorial Sloan-Kettering.

At present, clinicians rely on only a handful of known genetic biomarkers (early markers of disease) to predict outcome in leukemia patients, and these biomarkers provide useful information for only a subset of patients. For most people diagnosed with AML, it is difficult to predict the chance for a cure.

The method used in the study incorporates information from an array of genes and allows nearly two-thirds of patients to be categorized into clearly defined prognostic groups. Our goal was not to ask whether a certain gene or two raised or lowered risk, but to determine whether a combination of characteristics from a set of genes made it possible to precisely stratify patients according to risk, Dr. Levine says.

The researchers analyzed blood or bone marrow samples from 502 patients with AML who were participating in a clinical trial. Such samples are routinely taken for research purposes during trials with patient consent. The trial, led by Martin S. Tallman, MD, Chief of Memorial Sloan-Ketterings Leukemia Service, explored whether increasing the standard dose of chemotherapy in AML patients under age 60 would improve survival.

The team that performed the genetic analysis, which included investigators from Memorial Sloan-Kettering, Weill Cornell Medical College, and other institutions, analyzed the samples for abnormalities, or mutations, within 18 genes known to have alterations in people with AML. The researchers noted the relationship between the mutations present in each patient and how that patient ultimately fared with the disease receiving either the standard or increased chemotherapy dose.

Our findings have important clinical implications for patients with AML, demonstrating that genetic profiling can improve current prognostic models and help guide therapeutic decisions so patients have an optimal result, says Dr. Tallman, who is a co-author of the new study. Moving forward, the challenge will be to provide this genetic information in a timely and affordable way to influence treatment decisions prospectively, he adds.

The analysis allowed the researchers to determine specific risk levels for a variety of gene-mutation combinations. They also were able to establish that the higher chemotherapy dose used in the trial benefited only some of the patients. The investigators took into account variables such as patient age and gender and validated the results in a separate group of patients to ensure that the profiling approach will be generally applicable beyond the current trial.

Dr. Levine and his Memorial Sloan-Kettering colleagues are working to translate the results from the study into clinical use. Weve already developed genetic tests, which can be used to test for this set of mutations in patients, and were in the process of making sure they work well in practice, he says. We have preliminary evidence that they perform well, and were hoping to have a pilot study soon as a step toward getting it into the clinic. We want to show this approach can be used not just at Memorial Sloan-Kettering but throughout the leukemia community.

The American Cancer Society estimates that 13,780 people in the United States will be diagnosed with AML in 2012 and that more than 10,000 people will die from the disease.

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Genetic Profiling Can Help Doctors More Accurately Predict Prognosis and Guide Treatment Decisions for Leukemia Patients