Category Archives: Gene Medicine

Ever marvel at someone who smoked and still lived to be 90? Just plain good luck, researchers say. And those who live like Puritans and get cancer anyway?

Thats bad luck and its the primary cause of most cancer cases, says a Johns Hopkins Medicine research study.

Roughly two-thirds of cancer types in adults can be attributed to random mutations in genes capable of driving cancer growth, said two scientists who ran statistics on cancer cases.

That may sound jaw-dropping. And Johns Hopkins anticipates that the study will change the way people think about cancer risk factors.

They also believe it could lead to changes in the funding of cancer studies, with a greater focus on finding ways to detect those cancers attributed to random mutations in genes at early, curable stages.

Smoking can still kill you

But, no, thats not permission to smoke or to not use sunblock.

Some forms of cancer are exceptions, where lifestyle and environment play a big role. Lung cancer is one of them. So is skin cancer.

And, if cancer runs in your family, this unfortunately doesnt mean youre in the clear. Some cancers are more strongly influenced by genetic heritage than others.

The remaining third (of cancer types) are due to environmental factors and inherited genes, the Kimmel Cancer Center said in a statement on the study published Friday in the magazine Science.

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Scientists: Random gene mutations bad luck primary cause of most cancer types

Scientists from Case Western Reserve University's School of Medicine have discovered a potential treatment that may steer cancer cells toward their own destruction. The study focused on a particular gene that was found to influence levels of a tumor-fighting protein called 53BP1, the heightened presence of which makes cancer cells more vulnerable to existing forms of treatment.

The proposed therapeutic approach centers on the repairing of DNA, a process that sees the body mend molecules damaged by everything from reactive oxygen components to radiation and chemical agents. More specifically, it focuses on a double-strand break, a type of injury that sees both strands of the double helix severed, leading to damaged and dead cells.

One mechanism that the body uses to fix these double-strand breaks is gluing the DNA strands together again, but this isn't ideal as it renders those strands less effective in sending information through to the cell, meaning the cells are often left to die anyway. Another method of repair used by the body is using information from undamaged DNA to mend the broken DNA, a more effective way of repairing the broken double strands.

Through their study, the researchers observed the functions of an important gene in this process called UbcH7, known to help regulate the repair of broken double strands. What they found was that depleting levels of UbcH7 resulted in a significant boosting of the tumor-suppressing 53BP1 protein, which in turn drives the cancer cells toward the first, less effective path of repair: the gluing method. The team says the approach could complement current forms of treatment.

"What we propose is increasing the level of 53BP1 to force cancer cells into the error-prone pathway where they will die," says Youwei Zhang, assistant professor of pharmacology at the university's School of Medicine. "The idea is to suppress deliberately the second accurate repair pathway where cancer cells would prefer to go. It is a strategy that would lead to enhanced effectiveness of cancer therapy drugs.

The team's findings so far are the product of laboratory experiments, but the promising results has them planning on testing the approach in animal models. This would involve introducing the 53BP1 protein in mice and then treating them with radiation therapy and chemotherapy drugs.

The research findings were published in the journal Proceedings of the National Academy of Sciences.

Source: Case Western University

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New approach could lead cancer cells down path of destruction

Researchers have narrowed down the list of genes implicated in autism spectrum disorder, and they appear to point toward a part of the brain that has largely been overlooked.

Most research into the genetic roots of autism, a highly heritable disorder that affects about 1 in 68 children, starts with a kind of inventory of genes. Then, it narrows down this genome-wide survey to prime suspects that appear to be different among those with one or several of the symptoms of autism.

That gene-by-gene approach, however, has unearthed too many suspects, each with somewhat vague relationships to a small sliver of the autism spectrum. That situation has sparked some to abandon the gene-by-gene approach in favor of environmental factors that may alter gene behavior.

Whats special about autism is that it doesnt seem like its a one-gene thing, said Stanford UniversitySchool of Medicinegeneticist Michael Snyder, lead investigator of the study published online Tuesday in the journal Molecular Systems Biology.

Maybe this is a tough way to look at it, Snyder said of the gene-by-gene approach. Maybe a better way to look at it is to see what the normal biological landscape looks like, and see how people who are mutated for autism map onto that.

What followed was a complex computational task that corralled proteins into scores of modules tightly bound by their inter-related functions. Then Snyders team overlaid the map of gene variants implicated in autism.

At first glance, proteins encoded by these 383 suspect genes were scattered among many of these functional modules. But a few of the modules screamed out with autism connections, both from existing data and a genome screening the researchers conducted, Snyder said.

One module involved molecular activity that goes on all over the brain, particularly involving synapses, the tiny spaces where electrochemical signals cross for one neuron to another. This helps explain why so much autism research points toward problems with synapses.

But there was another module just as rich in autism implications, and this one implicated the corpus callosum. That thick band of fibers connects the brains two hemispheres, and its generally smaller among those with autism a disease marked by many anomalies in connectivity.

The corpus callosum is chock full of a different kind of brain cell, oligodendrocytes, which provide a sheath of insulation around the transmission lines of neurons, known as their axons. That greatly aids the propagation of electrochemical signals along the neuron. Defects in this myelin sheathing have been associated with developmentaldisorders.

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Study narrows down genetic suspects in autism

Published December 30, 2014

Scientists have begun clinical trials for the treatment of a gene mutation linked to multiple cancers, reveals a study published Tuesday in the journal Cancer Discovery.

In 1982, researchers discovered that the gene TRK caused a small percentage of colon cancers. In 2013 and 2014, studies linked the gene to at least 11 tumor types, including lung, breast and skin cancer. Modern technology has finally enabled researchers to test potential treatments for these gene abnormalities.

Now technology lets us find the gene in actual patient samples, and drugs are available to target these gene rearrangements making it possible to treat TRK cancers in clinical trials in ways we only dreamed of 32 years ago," Robert C. Doebele, investigator at the CU Cancer Center and associate professor of medical oncology at the CU School of Medicine, said in a news release.

In the womb, the TRK family of genes and the proteins they encode are crucial for the development and survival of neurons. After birth, they are programmed to go dormant, but when they improperly fuse with other nearby genes, the TRK genes can resume signaling cells to grow and become immortal. In adult tissue, this process can cause cancer.

"What we're finding is that while TRK fusions may not be the major cause in any single, major cancer, it's the cause of small percentages of many cancer types," Doebele said.

Doebeles study cites previous research that suggests TRK fusions are responsible for 3.3 percent of lung cancers, 1.5 percent of colorectal cancers, 12.3 percent of thyroid cancers, about 2 percent of glioblastomas, and 7.1 percent of pediatric gliomas (brain tumors). These numbers add up when they are considered together, Doebele said.

While treatments for TRK fusions were nonexistent a decade ago, today, a class of drugs has been developed to target this type of genetic abnormality. Tryrosine kinase inhibitors in particular can switch off these genes, and the Food and Drug Administration (FDA) has approved a drug that targets two different types of fusion genes in lung cancer.

"A lot of doctors in academia or community hospitals are ordering next-generation sequencing panels for their patients, Doebele said. If it turns out that patients' tumors have TRK alterations, I want their doctors to know that there are treatment options available via clinical trials.

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Scientists begin testing drugs for gene mutation linked to multiple cancers

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Newswise Case Western Reserve researchers have identified a two-pronged therapeutic approach that shows great potential for weakening and then defeating cancer cells. The teams complex mix of genetic and biochemical experiments unearthed a way to increase the presence of a tumor-suppressing protein which, in turn, gives it the strength to direct cancer cells toward a path that leads to their destruction.

If the laboratory findings are supported by tests in animal models, the breakthrough could hold the promise of increasing the effectiveness of radiation and chemotherapy in shrinking or even eliminating tumors. The key is to build up a good protein p53-binding protein 1 (53BP1) so that it weakens the cancer cells, leaving them more susceptible to existing cancer-fighting measures.

The breakthrough detailed appeared in the Nov. 24 online edition of the journal PNAS (Proceedings of the National Academy of Sciences).

Our discovery one day could lead to a gene therapy where extra amounts of 53BP1 will be generated to make cancer cells more vulnerable to cancer treatment, said senior author Youwei Zhang, PhD, assistant professor of pharmacology, Case Western Reserve University School of Medicine, and member of the Case Comprehensive Cancer Center. Alternatively, we could design molecules to increase levels of 53BP1 in cancers with the same cancer-killing end result.

The cornerstone of the research involves DNA repair more specifically, double-stand DNA repair. DNA damage is the consequence of an irregular change in the chemical structure of DNA, which in turn damages and even kills cells. The most lethal irregularity to DNA is the DNA double-strand break in the chromosome. DNA double-strand breaks are caused by everything from reactive oxygen components occurring with everyday bodily metabolism to more damaging assaults such as radiation or chemical agents.

The body operates two repair shops, or pathways, to fix these double strand breaks. One provides rapid, but incomplete repair namely, gluing the DNA strand ends back together. The problem with the glue method is that it leaves the DNA strands unable to transmit enough information for the cell to function properly leading to a high cell fatality rate.

The second shop, or pathway, uses information from intact, undamaged DNA to instruct damaged cells on how to mend broken double strands. During his study, Zhang and fellow investigators discovered a previously unidentified function of a known gene, UbcH7, in regulating DNA double-strand break repair. Specifically, they found that depleting UbcH7 led to a dramatic increase in the level of the 53BP1 protein.

What we propose is increasing the level of 53BP1 to force cancer cells into the error-prone pathway where they will die, Zhang said. The idea is to suppress deliberately the second accurate repair pathway where cancer cells would prefer to go. It is a strategy that would lead to enhanced effectiveness of cancer therapy drugs.

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Cancer Treatment Potential Discovered in Gene Repair Mechanism

Rhys Evans life could have been very different.

He could have been a bubble boy, forced to walk around in a protective see-through plastic canopy. You see, he was born with an immune system that barely worked. The slightest infection could have proved fatal. But Rhys is now 14years old and doing fine.

So how did Rhys avoid living in a bubble?

The simple answer is that Rhys got lucky his condition was diagnosed when he was a baby. Even more fortunately, doctors at Great Ormond Street Hospital were able to do something about it. They understood that Rhyss condition was caused by a genetic flaw and they thought that if they could correct this flaw then they could restore his immune system. That is exactly what happened, and why Rhys is now no different to any other young teenager.

Rhyss treatment is an example of gene therapy, which was the subject of a fascinating lecture that I attended last month. Leonard Seymour, professor of gene therapies in the Department of Oncology at Oxford University, gave four reasons why 2014 has been a breakthrough year for this revolutionary, but controversial, approach.

Let me begin by describing these successful trials.

Rhys Evans is not the only boy (it does not affect girls) to have received gene therapy for this syndrome 20 were given it at about the same time as Rhys. But he was lucky. In the trial, one in four ended up with leukaemia.

This year has seen the results of a new trial. In this, nine boys were treated and eight have been reported as still alive, 16 to 43 months after treatment. The ninth died from an infection already present when he began the gene therapy. Overall, the outcome is hugely promising and suggests that gene therapy could provide a permanent cure for patients who would otherwise receive a bone marrow transplant from a donor, with all the consequent risks of rejection.

HIV is a virus that weakens the immune system by destroying the white blood cells that fight disease and infection. In order to destroy the cells it has to enter them, and it does this via a protein called CCR5, found on the cell surface. Researchers have noticed that about 1% of patients contract HIV and yet come to no harm. The reason is that their cells have a rare genetic mutation which prevents them from displaying the CCR5 protein on their surface.

Now researchers have managed to engineer white blood cells so that they have this same rare mutation. They have injected billions of these genetically modified cells into 12 trial patients, and there is evidence that this procedure is safe and could suppress the virus.

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Why 2014 has been a breakthrough year for gene therapy

Published December 30, 2014

U.S. scientists have identified a molecular network of genes known to contribute to autism spectrum disorders, and they say their finding may help uncover new genes linked to these conditions.

"The study of autism disorders is extremely challenging due to the large number of clinical mutations that occur in hundreds of different human genes associated with autism," study author Michael Snyder, genetics and personalized medicine professor at Stanford University, said in a news release. "We therefore wanted to see to what extent shared molecular pathways are perturbed by the diverse set of mutations linked to autism in the hope of distilling tractable information that would benefit future studies."

According to the news release, researchers used gene expression data and genome sequencing to study the whole set of interactions within a cell, and they identified a module comprised of 119 proteins linked to autism genes.

The sequencing of the genomes was present in 25 study participants who had been diagnosed with autism, which confirmed the involvement of the module in autism. The autism candidate genes in the module were also present in more than 500 diagnosed patients who were analyzed by exome sequencing.

Researchers also found that the corpus callosum and oligodendrocyte cells in the brain can contribute to autism. Oligodendrocytes are myelin-forming cells of the central nervous system, and the corpus callosum is a huge band of myelinated fibers. Myelin, which is comprised of proteins and phospholipids, forms a sheath around nerve fibers and increases the speed at which impulses are conducted.

"In the future, we need to study how the interplay between different types of brain cells or different regions of the brain contribute to this disease, study author Jingjing Li, postdoctoral fellow at the Stanford Center for Genomics and Personalized Medicine, said in the news release.

Snyder said the module enriched in autism had two distinct components that exclusively interacted with each other: one that was expressed throughout different regions of the brain, and another that had enhanced molecular expression in the corpus callosum.

Based on their findings, the study authors hypothesized that disruptions in parts of the corpus callosum interfere with the circuitry that connects the two hemispheres of the brain, resulting in autism.

"Our study highlights the importance of building integrative models to study complex human diseases," Snyder said.

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US researchers identify gene network linked to autism

DALLAS -

Five-year-old Elizabeth Eastham has just finished a round of chemotherapy to treat kidney cancer. It's a tough battle, but Elizabeth's mom knows today's discoveries may bring tomorrow's hope.

"With what they find with your child can help another child later on would be fantastic," said Angela Eastham, Elizabeth's mother.

Dr. Hao Zhu is researching how pediatric cancers develop on the genetic level. He's pinpointed a gene that contributes to childhood cancers like neuroblastoma, Wilms tumor and liver cancer.

"And what we hope to do is to discover specific genetic targets for novel drugs to kill cancers without hurting the rest of the body," said Zhu, assistant professor Childrens Research Institute at UT Southwestern.

In laboratory mice, Zhu has found that the lin28 gene, which normally contributes to embryonic growth, also plays a role in cancer formation in fully developed juveniles.

"We hope one day to be able to treat and diagnose cancers better in children," Zhu explained.

"You don't want this for your child," said Eastham, "But you know that everything is in God's plan, and you know he saw us through this entire process and kept our strength up, and everyone's strength up around us to keep going and face one day at a time."

It may be years from the laboratory to the patient, but this discovery, published in the journal Cancer Cell, gives researchers hope that understanding how cancer works will lead to better treatments for children in the future.

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Health Beat: Cancer gene: Medicine's next big thing?

In 1982, the gene TRK was shown to cause a small percentage of colon cancers. In 2013 and 2014, next-generation sequencing of tumor samples found fusions of the TRK family of genes in at least 11 tumor types, including lung, breast, melanoma and more. Now, a recent article in the journal Cancer Discovery describes clinical trials at the University of Colorado Cancer Center and elsewhere that match drugs to this long-overlooked oncogene, offering targeted treatment options for cancers that harbor these gene abnormalities (e.g. ClinicalTrials.gov #NCT02122913).

"We didn't initially discover the gene. But now technology lets us find the gene in actual patient samples and drugs are available to target these gene rearrangements, making it possible to treat TRK cancers in clinical trials in ways we only dreamed of thirty-two years ago," says Robert C. Doebele, MD, PhD, investigator at the CU Cancer Center and associate professor of Medical Oncology at the CU School of Medicine.

The TRK family of genes, including NTRK1, NTRK2 and NTRK3 are important in the developing nervous system. In the womb, these genes and the proteins they encode are essential for the growth and survival of new neurons. After birth, these genes are unneeded in many tissues and so are programmed to go dormant. Some cancers wake them up - when improperly fused with other nearby genes, genes in the TRK family can restart their ability to signal cells to grow and become immortal, which in adult tissues can cause cancer.

"What we're finding is that while TRK fusions may not be the major cause in any single, major cancer, it's the cause of small percentages of many cancer types," Doebele says.

For example, the recent article cites studies showing NTRK fusions in 3.3 percent of lung cancers, 1.5 percent of colorectal cancers, 12.3 percent of thyroid cancers, about 2 percent of glioblastomas, and 7.1 percent of pediatric gliomas (brain tumors).

"These numbers add up," Doebele says.

A decade ago, the NTRK fusion and other, related gene rearrangements were un-druggable. Now, an entire class of drugs has been developed to target this type of genetic abnormality, namely "tyrosine kinase inhibitors," which are able to precisely turn off these genes like NTRK that send dangerously misplaced cell-survival signals. For example, the FDA-approved drug crizotinib targets ALK and ROS1 fusion genes in lung cancer.

A host of new drugs in this class of tyrosine kinase inhibitors target TRK fusions, for example investigational anti-cancer agents RXDX-101, TSR-011, LOXO-101, PLX-7486 and more.

"A lot of doctors in academia or community hospitals are ordering next-generation sequencing panels for their patients. If it turns out that patients' tumors have TRK alterations, I want their doctors to know that there are treatment options available via clinical trials," Doebele says.

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Cancer-causing mutation discovered in 1982 finally target of clinical trials

WASHINGTON: Scientists have found that whole-genome sequencing can be used to identify patients' risk for hereditary cancer.

In a first of its kind study, researchers at University of Texas Southwestern Medical Center used whole-genome sequencing to evaluate a series of 258 cancer patients' genomes to improve the ability to diagnose cancer-predisposing mutations.

"Whole-genome sequencing is a new genetic tool that can determine more of a person's DNA sequence than ever before," said Dr Theodora Ross, Professor of Internal Medicine and Director of UT Southwestern's Cancer Genetics Programme.

"Our results show that nearly 90 per cent of clinically identified mutations were confidently detected and additional cancer gene mutations were discovered, which together with the decreasing costs associated with whole-genome sequencing means that this method will improve patient care, as well as lead to discovery of new cancer genes," Ross said.

About 5 to 10 per cent of all cancers are caused by known inherited gene mutations. These mutations are passed down from generation to generation.

Mutations in the BRCA1 and BRCA2 genes are the most common cause of hereditary breast cancer. BRCA gene mutations are best known for their breast cancer risk, but they also cause increased risk for ovarian, prostate, pancreatic, and other cancers.

In addition, there are many different genes, including ATM, CDH1, CHEK2, PALB2, PTEN, and TP53, that are associated with an increased risk for breast cancer, and researchers are continually discovering additional genes that may affect cancer predisposition.

In the study, researchers developed new methods to analyse the large amount of data generated by whole-genome sequencing.

Ross' team devised a method to compare the group of patients with BRCA1 or BRCA2 mutations to a group of patients without BRCA mutations.

All expected BRCA1 and BRCA2 mutations were detected in the BRCA group, with at least 88.6 per cent of mutations confidently detected. In contrast, different cancer gene mutations were found in the cohort without BRCA mutations.

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Whole-genome sequencing can identify cancer-linked mutations