Category Archives: Gene Medicine

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Newswise HOUSTON -- (March 24, 2014) -- Scientists from Houston Methodist and Weill Cornell Medical College have found that a gene previously unassociated with breast cancer plays a pivotal role in the growth and progression of the triple negative form of the disease, which can be particularly deadly, with few treatment options. Their research, published in the April 3 Nature (online today), suggests that targeting the gene may be a new approach to treat the disease.

"We are really beginning to understand what initiates the cancer and why cancer cells evade treatment," said coauthor and Houston Methodist Cancer Center Director Jenny Chang, M.D. "Our group learned this pathway was activated in about two-thirds of patients with this type of breast cancer, and we believe we may be able to treat the disease by manipulating elements of the pathway."

About 42,000 new cases of triple negative breast cancer (TNBC) are diagnosed in the United States each year, about 20 percent of all breast cancer diagnoses. Patients who relapse typically do so within one to three years of being treated.

Senior author Laurie H. Glimcher, M.D., the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College, wanted to know whether the gene -- already understood from her prior work to be a critical regulator of immune and metabolic functions -- was important to cancer's ability to adapt and thrive in the oxygen- and nutrient-deprived environments inside of tumors. Using cells taken from patients' tumors and transplanted into mice, Glimcher's team found that the gene, XBP1, is especially active in TNBC, particularly in the progression of malignant cells and their resurgence after treatment.

"Patients with the triple negative form of breast cancer are those who most desperately need new approaches to treat their disease," said Glimcher, who is also a professor of medicine at Weill Cornell. "This pathway was activated in about two-thirds of patients with this type of breast cancer. Now that we better understand how this gene helps tumors proliferate and then return after a patient's initial treatment, we believe we can develop more effective therapies to shrink their growth and delay relapse."

The group, which included investigators from nine institutions, examined several types of breast cancer cell lines. They found that XBP1 was particularly active in basal-like breast cancer cells cultivated in the lab and in TNBC cells from patients. When they suppressed the activity of the gene in laboratory cell cultures and animal models, however, the researchers were able to dramatically reduce the size of tumors and the likelihood of relapse, especially when these approaches were used in conjunction with the chemotherapy drugs doxorubicin or paclitaxel. The finding suggests that XBP1 controls behaviors associated with tumor-initiating cells that have been implicated as the originators of tumors in a number of cancers, including that of the breast, supporting the hypothesis that combination therapy could be an effective treatment for TNBC.

The scientists also found that interactions between XBP1 and another transcriptional regulator, HIF1-alpha, spurs the cancer-driving proteins. Silencing XBP1 in the TNBC cell lines reduced the tumor cells' growth and other behaviors typical of metastasis.

"This starts to demonstrate how cancer cells co-opt the endoplasmic reticulum stress response pathway to allow tumors to grow and survive when they are deprived of nutrients and oxygen," said lead author Xi Chen, Ph.D., a postdoctoral associate at Weill Cornell, referring to the process by which healthy cells maintain their function. "It shows the interaction between two critical pathways to make the cells better able to deal with a hostile microenvironment, and in that way offers new strategies to target triple negative breast cancer."

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Triple Negative Breast Cancer's Progression and Relapse Pinned to a Gene

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Newswise NEW YORK, NY (March 21, 2014) Researchers at Columbia University Medical Center (CUMC) have devised a new system for classifying periodontal disease based on the genetic signature of affected tissue, rather than on clinical signs and symptoms. The new classification system, the first of its kind, may allow for earlier detection and more individualized treatment of severe periodontitis, before loss of teeth and supportive bone occurs. The findings were published recently in the online edition of the Journal of Dental Research.

Currently, periodontal disease is classified as either chronic or aggressive, based on clinical signs and symptoms, such as severity of gum swelling and extent of bone loss. However, there is much overlap between the two classes, said study leader Panos N. Papapanou, DDS, PhD, professor and chair of oral and diagnostic sciences at the College of Dental Medicine at CUMC. Many patients with severe symptoms can be effectively treated, while others with seemingly less severe infection may continue to lose support around their teeth even after therapy. Basically, we dont know whether a periodontal infection is truly aggressive until severe, irreversible damage has occurred.

Looking for a better way to classify periodontitis, Dr. Papapanou turned to cancer as a model. In recent years, cancer biologists have found that, in some cancers, clues to a tumors aggressiveness and responsiveness to treatment can be found in its genetic signature. To determine if similar patterns could be found in periodontal disease, the CUMC team performed genome-wide expression analyses of diseased gingival (gum) tissue taken from 120 patients with either chronic or aggressive periodontitis. The test group included both males and females ranging in age from 11 to 76 years.

The researchers found that, based on their gene expression signatures, the patients fell into two distinct clusters. The clusters did not align with the currently accepted periodontitis classification, said Dr. Papapanou. However, the two clusters did differ with respect to the extent and severity of periodontitis, with significantly more serious disease in Cluster 2. The study also found higher levels of infection by known oral pathogens, as well as a higher percentage of males, in Cluster 2 than in Cluster 1, in keeping with the well-established observation that severe periodontitis is more common in men than in women.

Our data suggest that molecular profiling of gingival tissues can indeed form the basis for the development of an alternative, pathobiology-based classification of periodontitis that correlates well with the clinical presentation of the disease, said Dr. Papapanou.

The researchers next goal is to conduct a prospective study to validate the new classification systems ability to predict disease outcome. The team also hopes to find simple surrogate biomarkers for the two clusters, as it would be impractical to perform genome-wide testing on every patient.

The new system could offer huge advantages for classifying people with different types of periodontitis. If a patient is found to be highly susceptible to severe periodontitis, we would be justified in using aggressive therapies, even though that person may have subclinical disease, said Dr. Papapanou. Now, we wait years to make this determination, and by then, significant damage to the tooth-supporting structures may have occurred.

The paper is titled, Gingival Tissue Transcriptomes Identify Distinct Periodontitis Phenotypes. The other contributors are M. Kebschull (CUMC), R.T. Demmer (CUMC), B. Grn (University of Linz, Linz, Austria), P. Guarnieri (CUMC), and P. Pavlidis (University of British Columbia, Vancouver, BC, Canada).

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Gene Expression Signature Reveals New Way to Classify Gum Disease

The same gene family that may have helped the human brain become larger and more complex than in any other animal also is linked to the severity of autism, according to new research from the University of Colorado Anschutz Medical Campus.

The gene family is made up of over 270 copies of a segment of DNA called DUF1220. DUF1220 codes for a protein domain -- a specific functionally important segment within a protein. The more copies of a specific DUF1220 subtype a person with autism has, the more severe the symptoms, according to a paper published in the PLoS Genetics.

This association of increasing copy number (dosage) of a gene-coding segment of DNA with increasing severity of autism is a first and suggests a focus for future research into the condition Autism Spectrum Disorder (ASD). ASD is a common behaviorally defined condition whose symptoms can vary widely -- that is why the word "spectrum" is part of the name. One federal study showed that ASD affects one in 88 children.

"Previously, we linked increasing DUF1220 dosage with the evolutionary expansion of the human brain," says James Sikela, PhD, a professor in the Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine. Sikela is the corresponding author of the study that was just published.

"One of the most well-established characteristics of autism is an abnormally rapid brain growth that occurs over the first few years of life. That feature fits very well with our previous work linking more copies of DUF1220 with increasing brain size. This suggests that more copies of DUF1220 may be helpful in certain situations but harmful in others."

The research team found that not only was DUF1220 linked to severity of autism overall, they found that as DUF1220 copy number increased, the severity of each of three main symptoms of the disorder -- social deficits, communicative impairments and repetitive behaviors -- became progressively worse.

In 2012, Sikela was the lead scientist of a multi-university team whose research established the link between DUF1220 and the rapid evolutionary expansion of the human brain. The work also implicated DUF1220 copy number in brain size both in normal populations as well as in microcephaly and macrocephaly (diseases involving brain size abnormalities).

The first author of the autism study, Jack Davis, PhD, who contributed to the project while a postdoctoral fellow in the Sikela lab, has a son with autism and thus had a very personal motivation to seek out the genetic factors that cause autism.

The research by Davis, Sikela and colleagues at the Anschutz campus in Aurora, Colo., focused on the presence of DUF1220 in 170 people with autism.

Strikingly, Davis says, DUF1220 is as common in people who do not have ASD as in people who do. So the link with severity is only in people who have the disorder.

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Gene family linked to brain evolution implicated in severity of autism symptoms

PUBLIC RELEASE DATE:

20-Mar-2014

Contact: Erin Digitale digitale@stanford.edu 650-724-9175 Stanford University Medical Center

STANFORD, Calif. Scientists and parents have worked together to identify a new genetic disease that causes neurologic, muscle, eye and liver problems in children. The discovery was unusually fast thanks to a combination of modern gene-sequencing techniques, social media and old-fashioned detective work.

One important clue was that affected children cry without making tears.

The new disease, called NGLY1 deficiency, is described in a paper that will be published online March 20 in Genetics in Medicine, the journal of the American College of Medical Genetics and Genomics. The paper describes eight children with mutations in the gene coding for N-glycanase 1, an enzyme that recycles defective products from a cellular assembly line. Children who lack this enzyme have varying degrees of movement disorders, including a characteristic combination of muscle contractions that causes abnormal tremulous movements. They also have developmental delays and liver problems. The gene defect is so rare that until recently, finding eight affected individuals would have taken several years; instead, the children were found in a matter of months.

"This represents a complete change in the way we're going about clinical medicine," said Gregory Enns, MB, ChB, associate professor of genetics in pediatrics at the Stanford University School of Medicine and co-lead author of the new paper. Gene-sequencing tools have sped the translation of findings between clinical and lab settings; in addition, scientists around the globe and lay people are contributing to the discovery process.

"This is happening so quickly because of the integration of the families with the researchers, and because so many people are coming at this from so many angles," said Enns, who is also a geneticist at Lucile Packard Children's Hospital Stanford and Stanford Children's Health. Other co-authors of the paper come from 12 research institutions across the United States, Canada, Germany and the United Kingdom.

"The relief of finally getting a diagnosis is just life-changing," said Kristen Wilsey, mother of Grace Wilsey, 4, who was the second American patient, and among the first few in the world, to be identified with NGLY1 deficiency. Grace's diagnosis was a pivotal moment not just for her San Francisco Bay Area family but also for defining the new disease, since the comparison of multiple patients allowed researchers to confirm that the disease existed.

The enzyme that is missing in NGLY1-deficiency patients is normally found in cells throughout the body. N-glycanase 1 helps break down incorrectly shaped proteins so their components can be reused. The new research confirmed that children with a defective NGLY1 gene do not make the N-glycanase enzyme. The researchers also observed that the children's liver biopsies contained an amorphous substance, which they suspected was an accumulation of protein that did not get recycled.

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Scientists, parents join forces to identify new genetic disease in children

Grace Wilsey was born with NGLY1 deficiency, which is caused by two mutations in the NGLY1 gene.

STORY HIGHLIGHTS

(CNN) -- What do you do when your baby lies limp in your arms, staring blankly into the distance while never crying?

What do you do when tests show signs of liver damage and your baby's seizures won't stop, but doctors can't tell you what's wrong or how to fix it?

Thanks to the Human Genome Project, which was completed in 2003, identifying new genetic mutations has gotten easier and cheaper. But geneticists often struggle to find patients who share these rare DNA quirks. Studying multiple patients with the same gene mutations and similar symptoms is crucial to identifying a new genetic disorder.

That's why a paper published Thursday in the journal Genetics in Medicine is so remarkable.

The paper identifies NGLY1 deficiency as an inherited genetic disorder, caused by mutations in the NGLY1 gene. The researchers have confirmed eight patients with these mutations who share several symptoms, including developmental delays, abnormal tear production and liver disease.

And they credit an "Internet blog" with bringing the patients and scientists together.

Grace's genome

Grace Wilsey's parents knew something was wrong right away. Their newborn daughter was lethargic. Her eyes seemed hollow and unfocused. She refused to eat. Doctors at the hospital ran multiple tests, but couldn't come up with a diagnosis.

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Kids who don't cry: New genetic disorder discovered

By Duke Medicine News and Communications

DURHAM, N.C. By combining the modern tools of gene-sequencing and social media, a team of researchers has confirmed the identification of a new genetic disorder that causes severe impairments in children.

The new disease, called NGLY1 deficiency, is reported online in the March 20, 2014, issue of Genetics in Medicine, the journal of the American College of Genetics and Genomics. The study describes the disease in eight patients, confirming the work of Duke Medicine scientists who originally identified the genetic mutation in a single young patient in 2012.

Children with the genetic mutation have a distinctive inability to produce tears when they cry, but also have movement disorders, developmental delays and liver problems. The genetic defect is so rare that without social media, the eight affected children would have remained unknown to each other and to scientists, but instead were connected within months.

After we got the original diagnosis, we worked really hard to find additional cases to confirm that we got it right, said senior author David Goldstein, Ph.D., director of the Center for Human Genome Variation at Duke. While we were working hard but making slow progress, the original family was writing about their experience and connecting with others on social media. They were able to find several more potential patients to be tested. This experience really brought home to all of us just how important family engagement is to this work and how important it is to think hard and long about every patients genome.

Duke researchers and scientists across two continents worked to sequence the entire genomes and exomes of the individual patients, revealing the newly identified genetic defect that was shared among them all.

The mutation causes a deficiency of the N-glycanase 1 enzyme, which is crucial in the process of recycling misshapen proteins so their components can be reused. In children with a defective NGLY1 gene, the proteins build up, resulting in impairments.

Because of the unusual clinical presentations - notably the absence of tears along with liver abnormalities - parents of other affected children in distant places recognized these features when they read social media posts by the original family, said co-lead author Vandana Shashi, M.D., a medical geneticist at Duke who evaluated the first patient. This enabled other children to be quickly identified and diagnosed.

After the first patient underwent sequencing at Duke, since NGLY1 had not yet been associated with human disease and since this was the only patient with mutations in the gene, Goldstein and Shashi consulted the Ad Hoc Genetics Committee at Duke. Charged with the task of advising Duke researchers on scientific and ethical issues related to genomic research, the committee reviewed the clinical and genomic data on the patient and approved the communication of the NGLY1 mutations to the family as likely causing the childs clinical symptoms.

"The Ad Hoc committee recognized that this study was venturing into uncharted territory, and we wanted to make the right decision, said Nancy C. Andrews, M.D., Ph.D., dean of the Duke University School of Medicine who chaired the ad hoc committee at the time of the decision. The guiding principle was that we had to do what was in the best interests of the patient and his family. I am delighted that this was how it turned out, and that this important discovery also benefits other patients around the world."

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Gene Sleuths and Social Media

A team of University researchers, lead in part by Cristen Willer, assistant professor of internal medicine, human genetics and computational medicine and bioinformation, published findings Sunday linking a previously unknown gene variation with healthier blood cholesterol levels and lower risk of cardiovascular disease.

The work expanded on research published by the same team in 2008 where they had found an association between a particular region of the genome the genetic material in an organisms cells and blood cholesterol levels. It then took six years for them to figure out exactly which gene in that region was responsible.

Willer, the senior author of the paper that was published in Nature Genetics, worked closely with a team of scientists and doctors around the world, including Kristian Hveem, a gastroenterologist at the Norwegian University of Science and Technology.

Through their work with the Norwegian scientists, Willer gained access to a Norwegian biobank of over 80,000 donated tissue samples, from which she and her team selected 10,000 samples to study. Willer said they chose people who had previously experienced a heart attack, and then a control sample of people who were the same age and sex as the first group, but hadnt had any heart problems.

Hveem said they were able to conduct a longitudinal, prospective follow-up study by collecting data from registries over many years without having to physically examine the patients after their initial registration.

The study design focused only on differences in DNA across people that also changed proteins.

By looking at that smaller set of all the DNA changes that are possible between individuals we were able to focus much more quickly on a specific gene called TM6SF2, Willer said.

To test their hypothesis that TM6SF2 was responsible for changing the blood cholesterol levels and risk of heart attack in the Norwegian subjects, the researchers disrupted the same gene in mice, either by overexpressing it or down-regulating it. The resulting effects in the mices blood cholesterol levels were exactly what the researchers had expected.

That was pretty clear evidence that this indeed was the gene responsible, Willer said.

Both Hveem and Willer plan to continue studying the gene in the hope that they may find a way to design a new drug that would target this gene in a way that hasnt been possible before.

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Blood cholesterol linked with new genetic variation

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Washington, March 18 : Researchers have discovered a previously unrecognized gene variation that makes humans have healthier blood lipid levels and reduced risk of heart attacks.

Researchers from the University of Michigan and the Norwegian University of Science and Technology scanned the genetic information available from a biobank of thousands of Norwegians, focusing on variations in genes that change the way proteins function.

Most of what they found turned out to be already known to affect cholesterol levels and other blood lipids.

But one gene, dubbed TM6SF2, wasn't on the radar at all. In a minority of the Norwegians who carried a particular change in the gene, blood lipid levels were much healthier and they had a lower rate of heart attack.

And when the researchers boosted or suppressed the gene in mice, they saw the same effect on the animals' blood lipid levels.

Cristen Willer, Ph.D., the senior author of the paper and an assistant professor of Internal Medicine, Human Genetics and Computational Medicine and Bioinformatics at the U-M Medical School, said that while genetic studies that focused on common variations may explain as much as 30 percent of the genetic component of lipid disorders, they still don't know where the rest of the genetic risk comes from.

She said that this approach of focusing on protein-changing variation may help them zero in on new genes faster.

Willer and Kristian Hveem of the Norwegian University of Science and Technology suggested the same gene may also be involved in regulating lipid levels in the liver.

The study has been published in the journal Nature Genetics.

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New gene linked to reduced heart attack risk discovered

Scientists have discovered a previously unrecognized gene variation that makes humans have healthier blood lipid levels and reduced risk of heart attacks -- a finding that opens the door to using this knowledge in testing or treatment of high cholesterol and other lipid disorders.

But even more significant is how they found the gene, which had been hiding in plain sight in previous hunts for genes that influence cardiovascular risk.

This region of DNA where it was found had been implicated as being important in controlling blood lipid levels in a report from several members of the same research team in 2008. But although this DNA region had many genes, none of them had any obvious link to blood lipid levels. The promise of an entirely new lipid-related gene took another six years and a new approach to find.

In a new paper in Nature Genetics, a team from the University of Michigan and the Norwegian University of Science and Technology report that they zeroed in on the gene in an entirely new way.

The team scanned the genetic information available from a biobank of thousands of Norwegians, focusing on variations in genes that change the way proteins function. Most of what they found turned out to be already known to affect cholesterol levels and other blood lipids.

But one gene, dubbed TM6SF2, wasn't on the radar at all. In a minority of the Norwegians who carried a particular change in the gene, blood lipid levels were much healthier and they had a lower rate of heart attack. And when the researchers boosted or suppressed the gene in mice, they saw the same effect on the animals' blood lipid levels.

"Cardiovascular disease presents such a huge impact on people's lives that we should leave no stone unturned in the search for the genes that cause heart attack," says Cristen Willer, Ph.D., the senior author of the paper and an assistant professor of Internal Medicine, Human Genetics and Computational Medicine & Bioinformatics at the U-M Medical School.

"While genetic studies that focused on common variations may explain as much as 30 percent of the genetic component of lipid disorders, we still don't know where the rest of the genetic risk comes from," Willer adds. "This approach of focusing on protein-changing variation may help us zero in on new genes faster."

Willer and Kristian Hveem of the Norwegian University of Science and Technology led the team that published the new result. Intriguingly, Willer and colleagues suggest the same gene may also be involved in regulating lipid levels in the liver -- a finding confirmed by the observations of a team led by Jonathan Cohen and Helen Hobbs, who propose a role for the gene in liver disease in the same issue of Nature Genetics.

Hveem, a gastroenterologist, says that "more research into the exact function of this protein will be needed to understand the role it plays in these two diseases, and whether it can be targeted with new drug therapies to reduce risk -- or treat -- one or both diseases."

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New gene linked to key heart attack risk factor found by novel gene-finding approach

A gene-by-gene examination of cells from one of the deadliest forms of brain cancer may have uncovered a new treatment option.

Neurosurgeon Clark Chen and his colleagues at the University of California San Diego School of Medicine decided to use a form of genetic engineering in which individuals genes in a cell are, in effect, turned off to see what impact this has on the cell.

In this case, Chen and his teams were applying this gene-silencing technique on cells from glioblastoma, one of the most aggressive and hard-to-treat malignant brain tumors. They were trying to find which genes played a key role in helping the cancerous brain cells grow and survive.

After compiling their list of genetic suspects, the U.C. San Diego researchers made an interesting discovery: Many of the genes involved in glioblastoma growth help regulate the effect of the neurochemical dopamine, they reported recently online in the journal Oncotarget.

Chen and his team made their discovery by using shRNA in a molecular engineering technique known as RNA interference. Called short-hairpin RNA by some and small-hairpin RNA by others, shRNA can keep a gene from turning the genetic blueprint encoded in its DNA into a specific protein molecule. Scientists use viruses to insert the shRNA into a target gene and block its role in the production of the protein.

ShRNAs are invaluable tools in the study of what genes do. They function like molecular erasers, said Chen, the vice chairman of the division of neurosurgery at the U.C. San Diego School of Medicine. We can design these erasers against every gene in the human genome.

Because of the similarities in the lists of genes involved in glioblastoma growth and dopamine regulation, the researchers decided to see what effect dopamine antagonist drugs would have on the brain cancer cells. They discovered these drugs have significant anti-tumor effects on glioblastoma cells grown in laboratory dishes and in lab mice.

The anti-glioblastoma effects of these drugs are completely unexpected and were only uncovered because we carried out an unbiased genetic screen, said Chen.

In addition to psychosis, dopamine antagonists are used to treat other disorders, including anxiety-panic and Parkinsons disease and to control nausea and vomiting and already have a stamp of approval from the U.S. Food and Drug Administration.

First, these drugs are already FDA-cleared for human use in the treatment of other diseases, so it is possible these drugs may be re-purposed for glioblastoma treatment, thereby bypassing years of pre-clinical testing, said Bob Carter, chairman of the U.C. San Diego School of Medicine division of neurosurgery.

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Anti-psychotic drug could help treat brain cancer