Category Archives: Genetic Medicine

Researchers may have found a molecule that inhibits the growth of a rare but fatal tumor that occurs in children, called diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine glioma (DIPG) is a pediatric brain tumor that mainly affects children under 10 years of age.

Approximately 300 children - usually between 5 and 9 years old - are diagnosed with DIPG every year. DIPGs are located in the brain's pons - a brain region that controls many of the body's vital functions, including breathing and heart rate.

DIPGs are extremely aggressive and difficult to treat, so being diagnosed with the tumor typically results in death within a year.

New research, however, offers hope for treating DIPG. Scientists from Northwestern University in Evanston, IL, may have found a molecule that could stop the development of the tumor. The team was led by Ali Shilatifard, Robert Francis Furchgott professor of biochemistry and pediatrics, and chair of biochemistry and molecular genetics at Northwestern University's Feinberg School of Medicine.

The new findings - published in the journal Nature Medicine - build on research that Shilatifard and colleagues have carried out in the past. Shilatifard and his team identified the pathway through which a genetic mutation causes cancer in a study published in the magazine Science, and a follow-up study - conducted in collaboration with Rintaro Hashizume and his team - used this knowledge to test the effects of pharmacological therapy on DIPG in mice.

The latter study inhibited the previously identified genetic pathway and successfully prolonged the life of mice by 20 days. The drug was administered through the mice's abdomen, but in this latest research, the team set out to investigate whether injecting the cells into the mice's brainstem would have more robust effects.

The scientists sampled tumor cell lines from an untreated patient and injected them into a mouse's brainstem, where it grew into a tumor. Subsequently, the scientists treated the mouse with a BET bromodomain inhibitor and went on to clinically monitor the tumor.

The BET bromodomain inhibitor has proven efficacious in several cancer models before.

In this study, by using the inhibitor, bromodomain proteins could no longer bind to the histone H3K27M - a mutant protein found in 80 percent of DIPG tumors. BET inhibitors stopped the proliferation of tumor cells, and forced them to differentiate into other cells instead. This successfully stopped tumor growth.

The study's first author, Andrea Piunti - a postdoctoral fellow in Shilatifard's laboratory in biochemistry and molecular genetics at Northwestern University Feinberg School of Medicine - suggests that BET inhibitors should next be tested in a pediatric trial to treat DIPG, especially since the drugs are already being tested for pediatric leukemia.

"To the best of our knowledge, this is the most effective molecule so far in treating this tumor. Every other therapy that has been tried so far has failed."

Ali Shilatifard, senior author

The senior author also notes that the currently available radiation therapy is ineffective in treating DIPG; it only adds a few months to the patients' survival.

Shilatifard comments on the importance of Northwestern University for making this research possible:

"This work could not have been done anywhere in the world except Northwestern Medicine, because of all the scientists and physicians who have been recruited here during the past five years and how they work together to link basic scientific research to the clinic," Shilatifard says. "This discovery is the perfect example of how we take basic science discoveries and translate them to cure diseases at Northwestern Medicine."

Learn how childhood cancer treatment may hinder later-life sexual relationships.

View post:
Rare but fatal pediatric brain tumor may be stopped with new molecule - Medical News Today

F

or doctors, the brochure from a California medical laboratory sounded like easy money: $30 for every person enrolled in a study of genetic tests meant to help select the best pain medication for each patient. A typical physician could make $144,000 a year in research fees.

But the clinical trial was largely a ploy to boost Proove Biosciencessrevenues, and many of the doctors who signed up did no actual work, say current and former employees.

Proove has grown rapidly by tapping into the public angst over surging opioid addiction. It is one of many companies touting personalized DNA-based tests backed by little or no credible scientific data showing their reliability. Thats because a regulatory loophole has left huge swaths of the multibillion-dollar genetic testing industry largely free of government oversight.

A STAT investigation found that Proove employees stationed in physicians offices pushed unnecessary tests on patients a practice called coercion by one former manager and they sometimes completed research evaluation forms on behalf of doctors, rating the tests as highly effective when they werent. In fact, Proove tests of DNA captured by swabbing inside a patients cheek were so unreliable that many physicians disregarded the results. There was scant evidence, said the companys former chief scientist, that the tests improved patient outcomes.

Called hogwash, a gene test for addiction risk exploits opioid fears

The company, located in two modern buildings in a burgeoning life sciences corridor in Irvine, Calif., also billed insurers in misleading ways to bump up payments, according to current and former employees and copies of insurance forms.

Promoting itself as the leader in personalized pain medicine, Proove claims its tests predict how patients will react to pain medicines and who might become dependent on opioids.

The company has enjoyed glowing television news coverage suggesting it can help combat the opioid crisis. Current and former employees and doctors who worked with Proove called such portrayals the product of hype generated by CEO Brian Meshkin, who lacks a background in science and is known for his consummate sales abilities and talent for self-promotion.

Meshkin is in it for the money. He wanted to swab as many people as possible, regardless of medical need, said Beth Stevens, a former Proove manager who left the company last year after clashing with the CEO. He wanted people who had a cold to be swabbed for opioid risk.

Meshkin declined an interview request and responded to only one of many written questions. In an emailed statement, he said, Proove is acting within the confines of the law [and intends] to follow both the letter and spirit of the law.

But legal experts told STAT that the way the company pays physicians involved in two ongoing Proove trials both key to the firms monthly revenues of roughly $2 million might violate anti-kickback laws.

STAT began its examination of Proove late last year, after being contacted by current and former employees who had read an article about the dearth of evidence supporting the companys flagship opioid risk test. The investigation included interviews with 12 current and former employees and four doctors who worked with Proove. STAT also obtained thousands of pages of internal memos, billing and insurance records, and reports of test results.

Separately, the FBI and the Office of Inspector General of the Department of Health and Human Services are investigating possible criminal wrongdoing by Proove, according to a former and a current employee who said they were recently interviewed by federal agents. They said the agents were focused on possible kickbacks involving payments to doctors. The FBI and HHS declined to comment.

The government has been concerned about companies marketing tests under the guise of research for several years. In 2014, HHS issued a fraud alert warning laboratories that some ways of paying doctors for research might violate laws against kickbacks for lab test referrals. The alert followed a spate of cases involving allegedly improper payments to doctors by laboratory companies.

In response to the HHS alert, Prooves legal counsel drafted a memo for executives and sales staff stipulating that company practices complied with the law. Among other arguments, it said Proove compensates doctors only for research they personally perform. But current and former employees and doctors who worked with Proove have since disputed that claim.

Dr. Titus Taube, a family practitioner in Warner Robins, Ga., said in an interview that when he signed up as a Proove researcher, It sounded like it was the wave of the future. He said he quickly became disillusioned and concluded that the pay was for referring patients to Proove for tests because the research tasks, including filling out questionnaires and assessing the tests efficacy, were done by a Proove employee at his office.

If doctors who order tests receive improper financial inducements through a research program such as compensation without working or payments based on the volume of referrals they make the company and doctors might be violating federal and state laws against kickbacks or other fraud, said Dr. R. Gregory Cochran, a physician and attorney with expertise on those statutes. Promoting inaccurate or unreliable tests could also leave a company vulnerable to claims of fraud and abuse, he said.

Proove conducts laboratory developed tests designed and used inside a single company or hospital lab that can be sold as long as they are ordered by a doctor. Last year, the Silicon Valley blood-testing firm Theranos became Exhibit A of what can go wrong with these tests: Its claims of rapid diagnosis of dozens of diseases from a tiny vial of blood were exposed as overblown. Theranos is now the subject of a federal criminal probe.

The Food and Drug Administration warned in 2015 that some laboratory developed tests harm patients by leading to erroneous diagnoses and treatments. But the agency withdrew proposed regulatory guidelines for these tests late last year, deferring to President Trumps yet-to-be named FDA commissioner and Congress to decide what, if any, rules to put in place.

The current gaps in oversight pose a challenge for the continued evolution of precision medicine, undermining patient and physician confidence and potentially slowing the adoption of validated tests, said Andrew Fish, who directs AdvaMedDx, a trade group for leading diagnostic-test developers.

For now at least, Proove and similar companies can sell tests without having to show that results are valid and meaningful. STAT obtained Proove laboratory reports with gene-test results for six patients that included numerous incompatible clinical recommendations.

In one case called typical by former and current employees a report cautioned that a patient was highly susceptible to breathing problems when given the powerful synthetic opioid fentanyl, yet suggested a normal dose. The records do not show if fentanyl was prescribed, or if the patient suffered harm from the recommendation.

Christopher Coston, who managed Proove research assistants in western states until his job was eliminated last March, said a lot of doctors looked at the reports and said, I dont think so. This doesnt make sense.

Dr. Oleg Gavrilyuk, a San Diego physical medicine specialist, defended Proove. Tests of how his patients would respond to particular drugs validate his clinical judgment most of the time, he said. When they dont, he ignores the results.

Ford created the first car, he said. Of course it was not perfect. Now Tesla is the state of the art. You cannot choke development based on the idea that its not perfect. Its the first step.

Prooves first clinical study subjected to peer review, based on data from 134 patients, wasnt published until late January in the Journal of Psychiatric Research. It found that doctors said most patients improved after treatment decisions guided by a Proove pain-perception test.

Genetic tests promised to help me achieve peak fitness. What I got was a fiasco

Dr. Eric Fung, a biotech executive who briefly served as the firms chief scientific officer in 2015 and coauthored the study, said in an interview that it emerged from an effort to mine Prooves database of tens of thousands of patient records for evidence of some kind of testing benefit. He acknowledged that the lack of a comparison group, made up of patients who did not get the test, weakens the findings.

Fung added that he left the company over doubts about the utility of its tests.

I could not find a good statistical or clinical benefit for these tests, he said. I didnt feel comfortable with the science being done at Proove.

The questionable science hasnt stopped Meshkin from building the privately held Proove into what Deloitte Consulting and Inc. magazine call one of the nations fastest-growing businesses. His formula is simple: recruit doctors as paid researchers, providing them with a financial stake in ordering tests for their patients.

Here is how it works, according to current and former employees: Proove conducts large trials two in progress aim to test 150,000 patients that ask clinicians to rate how much various Proove tests help patients.

Company sales representatives pitch research contracts to doctors, often targeting financially troubled practices that need a new revenue stream. They promise steady income for light work. Meshkin said last year that about 150 doctors had signed on, out of 400 who order Proove tests. But there has been substantial turnover as dissatisfied doctors drop out.

Proove places some of its 300 employees inside doctors offices, and instructs them to try to collect cheek-swab DNA samples from each patient and recruit them for clinical trials. Patients are informed that trial participants will not be billed for test fees, according to a current Proove employee. They also are supposed to tell patients their doctor has insisted on the tests.

Even patients without pain, seen at family medicine and OB-GYNpractices, were enlisted for pain- and addiction-related tests, Coston said. It seemed illogical, the former regional manager said, but Meshkin became angry when research assistants failed to sign up every patient.

Many doctors would test every single soul who walked in, said Coston. But they didnt do research. The doctor is steadily getting paid, and did nothing to deserve it except rent space to Proove.

Research assistants completed all research tasks at least half the time, said Stevens and other managers who supervised the assistants. Asked whether doctors profited from work they didnt do, she said, If it quacks like duck and it walks like a duck, it is.

Stevens said each research assistant had a quota of at least five cheek swabs a day. Documents obtained by STAT show they were offered escalating cash bonuses for meeting numerical goals above the quota.

Stevens called Meshkins tactics to push tests on patients who didnt need them coercion.

To avoid disrupting the flow of patients into exam rooms, the research assistants fly through patient surveys and consent forms. This leaves some patients feeling bullied, several former and current employees said.

Some research assistants grew uneasy with the high-pressure tactics and quit. People got tired of trying to get patients to participate who didnt want to participate, Stevens said.

Recruitment of patients became increasingly scripted and sales-oriented, said a current employee who spoke anonymously for fear of reprisals. Research assistants were told to avoid the word study when signing patients up for a trial, the employee said, after some objected to being used as guinea pigs.

The title research assistant was even changed to patient engagement representative, and Meshkin told managers to find attractive young people to fill that role, according to a former manager who spoke anonymously, citing a confidentiality agreement.

Crucially, Proove urges all doctors whether participating in a trial or not to sign a standing order for all their patients to get any Proove genetic tests, such as those for risk of opioid abuse, pain sensitivity, and response to opioids and other drugs.

Many doctors have been reluctant to sign. But by 2015 about 70 percent had done so under pressure from Meshkin, said the former manager. Examples of orders obtained by STAT authorize Proove research assistants to collect DNA from any patient under the doctors care.

How genetic testing of dubious value is infiltrating the world of sports

Meshkin emphasized that under a standing order, the decision to be tested is not up to [the patients], its up to the doctors, Stevens said that patients dont have a choice.

Standing orders are common in medicine, although not in such circumstances. Doctors often issue standing orders to streamline care when patients need regular tests or treatments for a known chronic condition. Such orders rarely apply to a wide range of genetic tests for all patients in a diverse practice.

Standing orders are often a red flag, particularly in a situation, like here, where the patients have varying diagnoses and needs, said Cochran, associate director of a joint health policy and law degree program at the University of California, San Francisco, and UC Hastings College of the Law. Theres absolutely a kickback concern if the doctor knows hes going to get a check based on the number of patients who sign up and get tested.

In his written statement, Meshkin said, Proove seeks to ensure that each participating clinician independently determines the medical necessity for tests, and that every patient signs an informed consent to have the testing performed.

The man behind the Proove enterprise has an elaborate personal website, featuring flattering photos of himself and his family. Effusive language praises his character, business acumen, and civic accomplishments as a former school board member, and the site lists his accolades, including an Entrepreneur of the Year award from the Orange County Business Journal in Southern California.

Volunteer. Public Servant. Entrepreneur. Coach. There are many words used to describe Brian Meshkin. But if you ask Brian, hes just Brian a guy who works hard, dreams big, and rolls up his sleeves to help others, the sites unsigned biography begins.

He also calls himself a published researcher, although he lacks any formal scientific training, and says nothing about the legal problems of a previous genetic testing venture.

That nutrigenomics company sold genetically customized dietary supplements through Las Vegas spas and directly to consumers. In an interview last year, Meshkin said he sold that company, Salugen, in 2009, soon after California authorities sent a cease-and-desist letter for improper marketing.

Hair testing for drug use gains traction but critics say the science needs to catch up

Former and current Proove doctors and employees said the site aptly captures a man who deeply believes in himself and grasps the power of spinning a good story.

Meshkin has been listed as a coauthor on study abstracts, Proove posters presented at scientific meetings, and the recently published study. His involvement in research was one of the reasons that Dr. Daniel A. Schwarz, Prooves former research and development director, said he decided to resign.

A Michigan pain specialist, Schwarz said he left Proove in 2015 over concerns about the companys lack of scientific integrity. You cant have a CEO trying to run the science who doesnt have a science background, he said. It was marketing. It wasnt science, and I couldnt be a part of that.

Schwarz said scientific control became a key issue when he began to doubt the validity of Prooves work and wanted to repair the companys research and development. Meshkin wasnt listening, he said. He didnt take the advice, and I felt that he just wanted to do it his way.

Schwarz also grew alarmed when coworkers said patient research records were not stored securely. Another former Proove executive, who requested anonymity due to a confidentiality agreement, said data sheets languished for long periods, stacked in heaps at Prooves main office.

The patient comes first, and if you have a product where you are not doing the right thing by the patient, I cant be a part of it, Schwarz said.

According to Stevens, company insiders hoped for vast improvements after Fung, a respected biotech executive who earned his MD and PhD degrees at Johns Hopkins University, was hired with fanfare in 2015.

I remember one of the clinical people who worked underneath [Fung] said to me, If he leaves this company, we all need to go, Stevens said.

Fung quit after three months.

Genetic testing fumbles, revealing dark side of precision medicine

Taube, the Georgia family doctor, said he saw firsthand how untrustworthy Prooves tests and studies are. He signed on with Proove about four months ago after he was approached by a sales rep. Taube said he was intrigued by Prooves ideas for advancing precision medicine and impressed by the support of Medicare and other insurers, described by Proove as study sponsors.

At first, he filled out the research forms himself, including an investigator intervention evaluation used to assess whether Proove tests helped patients or affected their care. But he said Proove managers told him, No, no, [the Proove employee] will take care of it.

This practice was widely adopted after some doctors filled out research forms partially or not at all, but still expected to be paid, said a former Proove executive who spoke anonymously due to a confidentiality agreement.

Taube then would sign the evaluations prepared by a Proove research assistant without giving them a close look. But he began to view the clinical trials as mostly marketing and looked more closely at the evaluations he signed. He was startled to see that Proove tests always received top ratings, though they were having little impact on his practice.

The results often were refuted by a patients experience, he said. For example, they showed that several of his patients should not take losartan, a blood pressure medicine, because they metabolized it poorly. But they had taken it successfully for years.

Taube recently stopped signing up new patients for Proove, saying he wondered, Can I trust the data?

His experience was typical, according to current and former Proove employees. They said Proove managers told representatives always to rate tests a 4 or 5 on a 5-point scale of benefit to the patient, even when a test had no bearing on clinical care.

Another former Proove executive, who also signed a confidentiality agreement, said even the principal investigator of a 50,000-patient Proove clinical trial Dr. Daniel R. Kendall, a McLean, Va., osteopath for National Spine & Pain Centers didnt rely on the tests. The former executive said an audit of 1,500 patient charts from Kendalls practice showed no changes in care based on Proove tests.

Via email, Kendall disputed that conclusion. He would not provide the audit and referred all questions to Proove. In his email statement, Meshkin said National Spine & Pain Center patients showed significant improvement in treatment, but did not provide any details.

Clinical trials helped increase testing, but insurers often rejected claims, leading Proove to devise another way to pump up its bottom line: creative billing.

Insurers deem many Proove tests experimental due to a lack of evidence that they could aid diagnosis or treatment of the patient. One consequence of the denials, said some former employees, is that Proove periodically stops paying many sales reps and even fires them.

Proove also has failed to pay many physicians, including Taube, for research services even doctors who actually did the work. Coston called it the main thing I was getting yelled about by my doctors. Taube said the company blamed slow insurance reimbursements.

By 2014, Proove could complete numerous tests using a single cheek swab. But insurance payments were less than what the company thought it could get for the same tests if they had been billed based on several different swabs, said current and former employees.

So Proove adopted a new billing strategy in 2015. Documents show that instead of submitting an invoice for multiple genetic tests from one date of service when the patients cheek was swabbed Proove unbundled the charges, dividing them up among several invoices keyed to the dates lab reports were issued. Current and former employees said this process has become the norm.

The company might bill insurers for its opioid risk test on Monday, for its pain perception test the following Monday, and so on suggesting that the patient was tested on several occasions. Combined billings were often in the range of $7,000 to $10,000.

A Southern California doctor, who would only comment anonymously, said he kicked Proove out of his practice. [T]hey billed the insurance four times more than what they told me they would bill initially. Several patients of mine became very upset at the unreasonable amount of money that they were charging the insurance company, the doctor said in an email. Such reactions were common among physicians, said current and former employees.

Michelle Cavanaugh, an expert with the California-based medical billing firm Kareo, called unbundling working the system.

What is the clinical justification for assigning it different dates? said P. Thomas Hirsch, president of Laboratory Billing Solutions in Portsmouth, N.H., after hearing a description of Prooves practices. If they cant give one, its just a scam.

Charles Piller can be reached at charles.piller@statnews.com Follow Charles on Twitter @cpiller

Link:
It's easy money: Lab offers doctors up to $144000 a year to push dubious genetic tests, employees say - STAT

Dr. Karsten Suhre of WCM-Q led a team of researchers that revealed links between genetic variations and serious diseases like Alzheimers, heart disease and cancer

A groundbreaking study by Weill Cornell Medicine-Qatar (WCM-Q) researchers has revealed many previously unknown links between genetic variations and a series of debilitating conditions, including Alzheimers disease, heart disease, autoimmune disorders and cancer.

A team of researchers led by WCM-Qs Dr. Karsten Suhre, Professor of Physiology and Biophysics, analyzed the genetic data of more than 1,300 individuals from Europe, Asia and the Middle East and identified over 450 genetic variants, many of which are involved in serious diseases.

However, the study went a step beyond conventional genome studies, which generally focus on simply attempting to identify genes which are associated with disease. In contrast, Dr. Suhres research aimed to understand in greater detail the many complex chemical processes involved in translating the information held within genes into the actual physical characteristics of diseases. Discovering the secrets of these intricate chemical processes known as pathways - is essential to provide a basis for the development of a new generation of drug therapies and more effective diagnostic tools for a host of complex diseases.

Dr. Suhre explained: Since the human genome was first mapped in its entirety in 2003, researchers have been working to understand the function of every gene in our body so that one day we can use this knowledge to truly cure complex diseases, like diabetes and cancer.

However, in order to translate this knowledge of the human genome into new drugs or treatment, it is not enough to simply know which genes are involved in a disease we know a lot of that already. Rather, we need to understand the roles that disease-associated genes play in the pathways that lead to disease. So the challenge for medical science in no longer to simply find out what genes are involved in which disease but to work out precisely how they are involved.

The groundbreaking study, entitled Connecting genetic risk to disease endpoints through the human blood plasma proteome, has now been published in the prestigious UK-based journal Nature Communication.

Explaining the research further, Dr. Suhre said that the human genome essentially acts as a series blueprints that tell the body how to produce the approximately 20,000 different proteins that are the building blocks of our body. In recognition of this, the research aimed to understand how variation in genes influences the proteins that are made from them and how this leads to disease. The WCM-Q research is different because in addition to analyzing the cohorts genomes and health states the study also examined more than 1,100 proteins.

Indeed, the project conducted the worlds first GWAS (genome-wide association study) to analyze more than 1,100 proteins in 1,300 individuals no previous study of this kind has analyzed such a large cohort nor so many different proteins.

To achieve such a large-scale study the researchers had to bring a protein measurement tool capable of handling very high volumes of data to Qatar for the very first time. The study marks the very first time the tool, provided by US-based company Somalogic, has ever been used outside of the USA. This platform is now available for use by all researchers in Qatar. Moreover, the blood samples used by the researchers were sourced from a previous study that was conducted in collaboration with the dermatology department of Hamad Medical Corporation in Qatar. The study also performed all genetic analyses through the WCM-Q genomics core facility. Importantly, the paper combined analysis of the genome, known as genomics, with analysis of an organisms proteins, known as proteomics. This combined approach, called multiomics, helps researchers understand the interactions between genes and the proteins that they encode.

Dr. Johannes Graumann, the WCM-Q researcher who implemented the Somalogic platform in Qatar, said: We are proud to say that this study was conceived and led by researchers in Qatar, and at institutions funded by the Qatar Foundation. It places Qatar firmly on the map as a major player in population studies with deep molecular phenotypes.

Dr. Khaled Machaca, Associate Dean for Research at WCM-Q, said: This novel multiomics approach combined genomics and proteomics in blood samples using cutting-edge technologies to link various disease to protein biomarkers in blood. This approach is not only powerful in better understanding disease development but also promises novel biomarker discovery especially for complex diseases. The ability to conduct such cutting-edge research under the auspices of Qatar Foundation is indeed extremely rewarding and aligns well with the goals set out in Qatar National Vision 2030.

Follow this link:
WCM-Q study pushes the boundaries of genetic medical research - Al-Bawaba

February 24, 2017 by Geri Clark Killer T cells surround a cancer cell. Credit: NIH

A newly discovered type of genetic mutation that occurs frequently in cancer cells may provide clues about the disease's origins and offer new therapeutic targets, according to research from Weill Cornell Medicine and the New York Genome Center.

Using next-generation sequencing technology, scientists have previously traced cancer's roots to mutations that disrupt the sequence of proteins. As a result, the cell either creates hyperactive or dysfunctional versions of proteins, or fails to produce them at all, leading to cancer. Now, a study published Jan. 12 in Cell illuminates a possible new type of driver of the disease: small (one- to 50-letter) insertions or deletions of DNA sequence, also called "indels," in regions of the genome that do not code for protein.

"Those noncoding regions are still important because they contain sequences that affect how genes are regulated, which is critical for normal cell development," said lead author Dr. Marcin Imielinski, an assistant professor of pathology and laboratory medicine at Weill Cornell Medicine and a core member at the New York Genome Center. "We already know they are biologically important. The question is whether they can impact cancer development."

In the study, Imielinski and his colleagues analyzed sequencing data from several publicly available databases of tumor samples, focusing on the 98 percent of the genome that does not code for protein. They initially looked at lung adenocarcinoma, the most common type of lung cancer, and found that the most frequent indel-mutated regions in their genomes landed in genes encoding surfactant proteins.

Though these genes are essential for healthy lung function, they had not previously been associated with lung cancer. However, they are highly and specifically expressed by the cell type that gives rise to lung adenocarcinoma.

The researchers then looked at the genomes of 12 other cancer types and found similar patterns in liver, stomach and thyroid tumors.

"In each cancer, noncoding indels clustered in genes that are critical to organ function, but had not been associated with the cancer," said Imielinski, who is also an assistant professor of computational genomics in the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

Most strikingly, these noncoding indels are very common, occurring in 20 to 50 percent of the associated cancers.

"They occur as frequently as the most famous cancer-causing mutations," said Imielinski, a paid consultant for the company 10X Genomics, which sells devices and technology to analyze genetic information. "Any gene or any sequence that mutated at this frequency has been shown to play a causal role in cancer. That would be an exciting outcome, if we can prove it."

Even if these mutations are not shown to cause cancer, they can be used in the future to improve cancer diagnosis and treatment.

"These mutations can be biomarkers that help us to diagnose a cancer early, or they could be used to pinpoint a primary cancer when there are metastases and we can't find the original cancer," Imielinski said. "There are a lot of potential clinical implications from these findings."

Explore further: Researchers pinpoint key regulatory role of noncoding genes in prostate cancer development

More information: Marcin Imielinski et al. Insertions and Deletions Target Lineage-Defining Genes in Human Cancers, Cell (2017). DOI: 10.1016/j.cell.2016.12.025

Journal reference: Cell

Provided by: Cornell University

Prostate cancer researchers studying genetic variations have pinpointed 45 genes associated with disease development and progression.

The steroid dexamethasone could potentially deter the growth of a prostate cancer subtype that was previously thought to be difficult to treat with medications, Weill Cornell Medicine researchers report. Their findings were ...

New research shows that current approaches to genome analysis systematically miss detecting a certain type of complex mutation in cancer patients' tumors. Further, a significant percentage of these complex mutations are found ...

Researchers from several major U.S. universities and ITMO University in Russia have identified a number of new driver mutations in lung cancer cells that may be responsive to genomically targeted therapies and to immunotherapy.

A Yale-led study describes how a known cancer gene, EGFR, silences genes that typically suppress tumors. The finding, published in Cell Reports, may lead to the development of more effective, individualized treatment for ...

Short, unstable stretches of DNA, called microsatellites, may play a far greater role in the development and progression of cancer than previously thought, UW Medicine researchers report in a study appearing Oct. 3 in the ...

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

See more here:
Discovery of genetic mutation may boost cancer therapies - Medical Xpress

Photo: Carol Kaliff / Carol Kaliff

Boehringer Ingelheim's North American headquarters located in Ridgefield, CT.

Boehringer Ingelheim's North American headquarters located in Ridgefield, CT.

BI announces COPD collaboration with Weill Cornell Medicine

RIDGEFIELD Boehringer Ingelheim announced a collaboration with Weill Cornell Medicine to identify new treatment approaches for chronic obstructive pulmonary disease, also known as COPD, with the hopes of halting or reversing the progression of the disease.

The three-year collaboration combines Weill Cornell Medicines Department of Genetic Medicines understanding of chronic airway diseases and use of novel therapeutic concepts for airway repair with BIs knowledge in the discovery and development of new therapies for respiratory diseases.

It is the second collaboration between BI and Weill Cornell Medicine, following prior work in inflammatory bowel disease.

The scientists at Weill Cornell Medicine and Boehringer Ingelheim will work hand in hand to translate new discoveries into drug discovery and development programs at Boehringer Ingelheim, Dr. Clive R. Wood, senior corporate vice president, Discovery Research at BI, said in a release.

The new collaboration is an excellent example of our unique partnering approach and our focus on early innovation, underscoring our ambition to develop the next generation of medical treatments for patients with COPD.

Chronic lower respiratory diseases, which include COPD, are the third leading cause of death in the United States. Approximately 15 million Americans have been told by a health care provider that they have COPD, BI officials said.

The goal of the new treatment is to help patients keep as active as possible and improve their overall quality of life, BI officials said.

Our continuous search for molecular drivers of chronic obstructive airway diseases has revealed novel repair mechanisms that warrant further investigation of their potential as therapeutic approaches, Dr. Ronald G. Crystal, chairman of Genetic Medicine at Weill Cornell Medicine and lead investigator in the new collaboration, said in a release.

BI is based in Ridgefield and employs about 2,500 people locally.

cbosak@hearstmediact.com; 203-731-3338

Continue reading here:
BI announces COPD collaboration with Weill Cornell Medicine - Danbury News Times

February 24, 2017 Dr. Pengfei Liu holding human DNA treated with fluorescent dyes prepared for copy number variant analysis. Credit: Baylor College of Medicine

The genetic material of an organism encodes the instructions that guide its development. These codes are not written in stone; they can change or mutate any time during the life of the organism. Single changes in the code can occur spontaneously, as a mutation, causing developmental problems. Others, as an international team of researchers has discovered, are too numerous to be explained by random mutation processes present in the general population. When such multiple genetic changes occur before or early after conception, they may inform scientists about fundamental knowledge underlying many diseases. The study appears in Cell.

"As a part of the clinical evaluation of young patients with a variety of developmental issues, we performed clinical genomic studies and analyzed the genetic material of more than 60,000 individuals. Most of the samples were analyzed at Baylor Genetics laboratories," said lead author Dr. Pengfei Liu, assistant professor of molecular and human genetics Baylor College of Medicine and assistant laboratory director of Baylor Genetics. "Of these samples, five had extreme numbers of genetic changes that could not be explained by random events alone."

The researchers looked at a type of genetic change called copy number variants, which refers to the number of copies of genes in human DNA. Normally we each have two copies of each gene located on a pair of homologous chromosomes.

"Copy number variants in human DNA can be compared to repeated or missing paragraphs or pages of text in a book," said senior author Dr. James R. Lupski, Cullen Professor of Molecular and Human Genetics at Baylor. "For instance, if one or two pages are duplicated in a book it could be explained by random mistakes. On the other hand, if 10 different pages are duplicated, you have to suspect that it did not happen by chance. We want to understand the basic mechanism underlying these multiple new copy number variant mutations in the human genome."

A rare, early and transitory phenomenon that can affect human development

The researchers call this phenomenon multiple de novo copy number variants. As the name indicates, the copy number variants are many and new (de novo). The latter means that the patients carrying the genetic changes did not inherit them from their parents because neither the mother nor the father carries the changes.

In this rare phenomenon, the copy number variants are predominantly gains duplications and triplications rather than losses of genetic material, and are present in all the cells of the child. The last piece of evidence together with the fact that the parents do not carry the alterations suggest that the extra copies of genes may have occurred either in the sperm or the egg, the parent's germ cells, and before or very early after fertilization.

"This burst of genetic changes happens only during the early stages of embryonic development and then it stops," Liu said. "Interestingly, despite having a large number of mutations, the young patients present with relatively mild neurological problems."

The researchers are analyzing more patient samples looking for additional cases of multiple copy number variants to continue their investigation of what may trigger this rare phenomenon.

"We hope that as more researchers around the world learn about this and confirm it, the number of cases will increase," Liu said. "This will improve our understanding of the underlying mechanism and of why and how pathogenic copy number variants arise not only in developmental disorders but in cancers."

A new era of clinical genomics-supported medicine and research

This discovery was made possible in great measure thanks to the breadth of genetic testing performed and genomic data available at Baylor Genetics laboratory.

"The diagnostics lab Baylor Genetics is one of the pioneers in this new era of clinical genomics-supported medical practice and disease gene discovery research," Lupski said. "They are developing the clinical genomics necessary to foster and support the Precision Medicine Initiative of the National Institutes of Health, and generating the genomics data that further drives human genome research."

Using state-of-the art technologies and highly-trained personnel, Baylor Genetics analyzes hundreds of samples daily for genetic evaluation of patients with conditions suspected to have underlying genetic factors potentially contributing to their disease. Having this wealth of information and insight into the genetic mechanisms of disease offers now the possibility of advancing medicine and basic research in ways that were not available before.

"There is so much that both clinicians and researchers can learn from the data generated in diagnostic labs," Liu said. "Clinicians receive genomic information that can aid in diagnosis and treatment of their patients, and researchers gather data that can help them unveil the mechanisms underlying the biological perturbations resulting in the patients' conditions."

Explore further: Largest study of its kind finds rare genetic variations linked to schizophrenia

More information: An Organismal CNV Mutator Phenotype Restricted to Early Human Development. Cell, DOI: dx.doi.org/10.1016/j.cell.2017.01.037

Journal reference: Cell

Provided by: Baylor College of Medicine

Many of the genetic variations that increase risk for schizophrenia are rare, making it difficult to study their role in the disease. To overcome this, the Psychiatric Genomics Consortium, an international team led by Jonathan ...

Scientists at Baylor College of Medicine, Baylor Genetics, the University of Texas Health Science Center at Houston and Texas Children's Hospital are combining descriptions of patients' clinical features with their complex ...

Scientists have linked a gene called PKD1L1 with disarrangement of human internal organs, known as laterality defects, and complex congenital heart disease. This discovery contributes to a better understanding of the genetic ...

A team of scientists from a number of institutions around the world, including Baylor College of Medicine, has discovered that rare neurological syndromes for which there was no cause can be the result of variations in the ...

A team of researchers at Baylor College of Medicine has developed a family-based association test that improves the detection in families of rare disease-causing variants of genes involved in complex conditions such as Alzheimer's. ...

An international team of scientists has identified variants of the gene EBF3 causing a developmental disorder with features in common with autism. Identification of these gene variants leads to a better understanding of these ...

The genetic material of an organism encodes the instructions that guide its development. These codes are not written in stone; they can change or mutate any time during the life of the organism. Single changes in the code ...

A research team from the United States and Canada has developed and successfully tested new computational software that determines whether a human DNA sample includes an epigenetic add-on linked to cancer and other adverse ...

Gene discovery research is uncovering new information about similarities and differences underlying various neurodevelopmental disorders.

Our genes play a significant role in how anxious we feel when faced with spatial and mathematical tasks, such as reading a map or solving a geometry problem, according to a new study by researchers from King's College London.

A University of Toronto (U of T) study on fruit flies has uncovered a gene that could play a key role in obesity in humans.

Gene editing techniques developed in the last five years could help in the battle against cancer and inherited diseases, a University of Exeter scientist says.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Continue reading here:
Scientists find a striking number of genetic changes can occur early ... - Medical Xpress