A genetic analysis led by UT Southwestern Medical Center researchers suggests that most pancreatic cancers harbour genetic alterations that could be targeted by existing drugs, using their genetic features as a roadmap for treatment. The findings support a precision approach to treating pancreatic cancer, the fourth most deadly cancer for both men and women.
A comprehensive DNA sequencing of pancreatic cancer cases revealed not only a plethora of damaged genes, but potential diagnostic biomarkers that could help identify those with longer or shorter survival, and provide opportunity for new therapeutic interventions.
“We identified a wealth of genetic diversity, including multiple mutated genes that were previously unknown to pancreatic cancer − an important step in gaining a better understanding of this difficult and particularly deadly disease,” said lead author Dr. Agnieszka Witkiewicz, Associate Professor of Pathology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. “Importantly, the team was able to identify several genes that may be able to help us to predict outcomes in certain circumstances or serve as good candidates for therapeutic efforts.”
Researchers have long hoped that genetic analysis would provide insight into the biology of pancreatic cancer and define new targets for more effective treatment. Achieving this goal has been hampered by the technical difficulty of isolating pure cancer cells out of the tumour tissue that contains both tumour cells as well as normal cells. The new study overcame this limitation by selectively dissecting cancer cells from pieces of tumour tissue. This method was applied to specifically determine the genetic features of 109 different tumours.
The data showed that the genetic architecture of pancreatic cancer is complex, and each patient’s tumour was found to be unique. The genetic features illuminated ways in which the disease arises, defined events associated with survival, and yielded potential targets for therapeutic intervention.
“While we suspect that genetics can be used as the basis of targeted treatments, this point will only be proven through extensive research and clinical studies, hopefully leading to improved outcomes for patients,” said senior author Dr. Erik Knudsen, Professor of Pathology, and member of the Simmons Cancer Center who holds the Dr. Charles T. Ashworth Professorship in Pathology. “I am considerably more optimistic of the utility of a genetically targeted therapy for pancreatic cancer today than when we began this work.”
Pancreatic cancer is particularly difficult to treat, and is often diagnosed at a late stage when it is no longer amenable to surgical removal. Chemotherapy has a modest effect, and unfortunately the disease progresses in the vast majority of cases. Therefore, new therapeutic regimens are urgently needed.
UT Southwestern Medical Center
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Building on their discovery of a gene linked to eating disorders in humans, a team of researchers at the University of Iowa has now shown that loss of the gene in mice leads to several behavioural abnormalities that resemble behaviours seen in people with anorexia nervosa.
The team, led by Michael Lutter, MD, PhD, assistant professor of psychiatry in the UI Carver College of Medicine, found that mice that lack the oestrogen-related receptor alpha (ESRRA) gene are less motivated to seek out high-fat food when they are hungry and have abnormal social interactions. The effect was stronger in female mice, which also showed increased obsessive-compulsive-like behaviours.
The study also shows that ESRRA levels are controlled by energy status in the mice. Restricting calorie intake to 60 percent of normal over several days significantly increased levels of ESRRA in the brains of normal mice.
“Decreased calorie intake usually motivates animals, including humans, to seek out high-calorie food. These findings suggest that loss of ESRRA activity may disrupt that response,” Lutter says.
Anorexia nervosa and bulimia nervosa are common and severe mental illnesses. Lutter notes that although 50 to 70 percent of the risk of getting an eating disorder is inherited, identifying the genes that mediate this risk has proven difficult. Learn more about the treatment of eating disorders at UI Hospitals and Clinics.
ESRRA is a transcription factor—a gene that turns on other genes. Lutter and his colleagues previously found that a mutation that reduces ESRRA activity is associated with an increased risk for eating disorders in human patients. Although ESRRA is expressed in many brain regions that are disrupted in anorexia, almost nothing was known about its function in the brain. In the new study Lutter’s team manipulated ESRRA in mice to investigate the gene’s role in behaviour.
University of Iowa Hospitals and Clinics
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Innovative gastric cancer-detection technology can be used for the early detection of stomach cancer and for identifying persons at risk for developing the disease. The new detection method, based on breath analysis, has significant advantages over the existing detection technology.
Gastric cancer is one of the most lethal forms of cancer and in most cases, its diagnosis involves an endoscopy (the insertion of a tube into the oesophagus, requiring that the patient fast and receive an intravenous sedative). Treatment is aggressive chemotherapy, radiation and the full or partial removal of the stomach. The disease develops in a series of well-defined steps, but there’s currently no effective, reliable, and non-invasive screening test for picking up these changes early on. Thus, many people succumb to stomach cancer only because it was not diagnosed in time.
The new technology, developed by Prof. Hossam Haick of the Technion Faculty of Chemical Engineering, can be used to detect premalignant lesions at the earliest stage, when healthy cells start becoming cancerous.
The research, published as part of the doctoral thesis of Mr. Haitham Amal, was conducted in conjunction with a Latvian research group headed by Prof. Marcis Leja, based on the largest population sample ever in a trial of this type. 484 people participated in the trial, 99 of whom had already been diagnosed with stomach cancer. All the participants were tested for Helicobacter pylori, a bacterium known to increase the risk for stomach cancer, and two breath samples were taken from each person.
The first sample from each participant was analysed using the GCMS technique, which measures volatile organic substances in exhaled breath. The researchers noted that GCMS technology cannot be used to detect stomach cancer because the testing is very expensive and requires lengthy processing times and considerable expertise to operate the equipment.
The second breath sample was tested using nanoarray analysis, the unique technology developed by Prof. Haick, combined with a pattern recognition algorithm.
The findings:
Based on the concentrations of 8 specific substances (out of 130) in the oral cavity, the new technology can distinguish between three groups: gastric cancer patients, persons who have precancerous stomach lesions, and healthy individuals.
The new technology accurately distinguishes between the various pre-malignant stages.
The new technology can be used to identify persons at risk for developing gastric cancer.
The diagnosis is accurate, regardless of other factors such as age, sex, smoking habits, alcohol consumption and the use of anti-oxidant drugs.
In short, the nano-array analysis method developed by Prof. Haick is accurate, sensitive technology that provides a simple and inexpensive alternative to existing tests (such as GCMS). This new technology offers early, effective detection of persons at risk for developing stomach cancer, without unnecessary invasive tests (endoscopy). In order to assess the accuracy and effectiveness of the new, a wide-scale clinical trial is currently under way in Europe, with thousands of participants who have cancerous or pre-cancerous tumours.
Technion
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A new method for measuring genetic variability within a tumour might one day help doctors identify patients with aggressive cancers that are more likely to resist therapy, according to a study led by researchers now at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).
Researchers used a new scoring method they developed called MATH (mutant-allele tumour heterogeneity) to measure the genetic variability among cancer cells within tumours from 305 patients with head and neck cancer. High MATH scores corresponded to tumours with many differences among the gene mutations present in different cancer cells.
Cancers that showed high genetic variability – called ‘intra-tumour heterogeneity’ – correlated with lower patient survival. If prospective studies verify the findings, MATH scores could help identify the most effective treatment for patients and predict a patient’s prognosis.
Researchers have long hypothesized that multiple sub-populations of mutated cells within a single cancer lead to worse clinical outcomes; however, oncologists do not use tumour heterogeneity to guide clinical care decisions or assess disease prognosis because there is no single, easy-to-implement method of doing so in clinical practice.
To address this need, James Rocco, MD, PhD, and his colleagues developed MATH to make it easier for doctors to measure genetic variability in patients’ tumours and to help guide treatment decisions.
The new findings confirm that high genetic variability with a patient’s tumour is related to increased mortality in head and neck squamous cell carcinoma.
‘Genetic variability within tumours is likely why people fail treatment,’ says Rocco, Professor and John and Mary Alford Chair of Head and Neck Surgery and Director of the OSUCCC – James Division of Head and Neck Oncologic Surgery. ‘In patients who have high heterogeneity tumours it is likely that there are several clusters of underlying mutations – in the same tumour – driving the cancer. So their tumours are likely to have some cells that are already resistant to any particular therapy.’
For the current study, Rocco and his team used the MATH tool to analyse retrospective data from 305 head and neck squamous cell carcinoma patients from The Cancer Genome Atlas (TCGA). This National Institutes of Health repository of publicly available data was launched in 2006 as a pilot project and now includes samples from more than 11,000 patients across 33 tumour types. The MATH score was calculated from data obtained by TCGA with a genome sequencing technique called whole-exome sequencing.
Researchers confirmed that high intra-tumour heterogeneity was related to increased mortality in this sub segment of patients. Each 10 percent increase in MATH score corresponded to an 8.8 percent increased likelihood of death.
The relationship between MATH score and mortality was not dependent on HPV (human papilloma virus) status or other molecular characteristics of the tumour.
‘Our retrospective analysis showed that patients with high heterogeneity tumours were more than twice as likely to die compared to patients with low heterogeneity tumors,’ says Rocco. ‘This type of information could refine the dialogue about how we tackle cancer by helping us predict a patient’s treatment success and justify clinical decisions based on the unique makeup of a patient’s tumor.’
EurekAlert
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In a recent study, Virginia Commonwealth University School of Medicine researchers predicted which cirrhosis patients would suffer inflammations and require hospitalization by analysing their saliva, revealing a new target for research into a disease that accounts for more than 30,000 deaths in the United States each year.
The findings could trigger a change in the way researchers study chronic liver disease and associated microbiota, the network of tiny organisms in the human body such as bacteria and fungi that can either bolster an immune system or weaken it.
The breakdown of defences in the mucosa of the gut has long been a signal of inflammation in those with cirrhosis, which sees healthy liver tissue replaced by scar tissue.
The recent findings suggest that another part of the body also can produce warning signs.
“It has been believed that most of the pathogenesis of cirrhosis starts in the gut, which is what makes this discovery so fascinating,” said Jasmohan S. Bajaj, M.D., associate professor of hepatology in the VCU School of Medicine and Hunter Holmes McGuire Veterans Affairs Medical Center.“The fact that saliva, along with fluid in the gut, can be an indicator of inflammation tells us that we need to further explore the oral cavity and its connections to liver disease.”
The paper describes a study of more than 100 cirrhosis patients from VCU and VA Medical Center, 38 of which had to be hospitalized within 90 days because of flare-ups. Researchers found that the ratio of good-to-bad microbes was similar in the saliva as in the stool of these patients who required hospitalization.
Another part of the same study looked at an additional group of more than 80 people with and without cirrhosis. Those with cirrhosis had impaired salivary defenses, mirroring the immune deficiencies that take place in the gut.
“The data suggest that there may be a change in the overall mucosal-immune interface in cirrhosis patients, allowing a more toxic microbiota to emerge in both the gut and oral cavity,” said Phillip B. Hylemon, Ph.D., professor of microbiology and immunology in the VCU School of Medicine and co-author of the paper.
In addition to using oral microbiota to predict the disease status of cirrhosis patients, Hylemon said the new evidence could provide a useful tool for testing treatment protocols for patients with cirrhosis or other diseases driven by inflammation.
Virginia Commonwealth University Scool of Medicine
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Smokers with a specific genetic variation are more likely to keep smoking longer than those who don’t have the gene variant, new research indicates. They’re also more likely to be diagnosed with lung cancer at a younger age.
Researchers at Washington University School of Medicine in St. Louis led an analysis of 24 studies involving more than 29,000 smokers of European ancestry and found that smokers with a particular variation in a nicotine receptor gene were more likely to continue smoking for four years after those without the variant had quit. Those with the genetic variant also were more likely to be diagnosed with lung cancer four years earlier than those without the variation in the CHRNA5 gene.
The findings may result in changes to efforts to screen patients for lung cancer.
“People with the risk variant average a four-year delay in the age at which they quit smoking,” said first author Li-Shiun Chen, MD. “Instead of quitting at age 52, which was the average age when study participants with a normal gene stopped smoking, people with the genetic variant quit at age 56.”
Chen said those with the gene variant also tend to inhale more deeply when they smoke. That combination of genes and behaviour contributes to the development of lung cancer earlier in life.
“They are likely to be diagnosed four years earlier,” she said. “In those with lung cancer, the average smoker without the gene variant is diagnosed at age 65. Those with the greater genetic risk tend to be diagnosed at 61.”
Chen said the presence of the gene variation has important clinical implications. Smokers who have the gene variant could undergo lung cancer screening at a younger age, she said. In addition, previous work from Chen and senior investigator Laura Jean Bierut, MD, shows that those with the gene variant are more likely to respond to medications that help people quit smoking, so knowing more about a smoker’s genetic makeup could help guide that individual’s therapy.
“The same people with this high-risk gene are more likely to respond to smoking-cessation medications, such as nicotine-replacement patches, lozenges or gum,” Chen said. “Although it’s clear the gene increases the chances a person will develop lung cancer at a younger age, it also is clear that the risk can be reversed with treatment.”
Washington University in St Louis
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Cancer DNA circulating in the bloodstream of lung cancer patients can provide doctors with vital mutation information that can help optimise treatment when tumour tissue is not available, an international group of researchers has reported at the European Lung Cancer Conference (ELCC) in Geneva, Switzerland.
The results have important implications for the use of cancer therapies that target specific cancer mutations, explains Dr Martin Reck from the Department of Thoracic Oncology at Lung Clinic Grosshansdorf, Germany, who presented the findings at the conference.
Testing for the presence of these mutations in the tumour itself is not always possible, however studies have suggested that DNA from the tumour that circulates in the bloodstream of patients may provide similar information.
The large international ASSESS study aimed to compare the ability of blood testing to detect EGFR mutations with the more standard method of testing the tumour itself.
“We were really asking a question on behalf of patients,” Reck said: “Is there a valid test that can identify an EGFR mutation and give me the opportunity for superior treatment, even if my lung tumour is not accessible for bronchoscopy or CT-guided biopsy? And, are the results of this blood test in agreement with the results of the ‘gold-standard’ tissue test?”
Overall, the study included 1162 matched tissue and blood samples. Comparison of the outcomes of EGFR testing in the two techniques showed an 89% rate of agreement between the blood test and tissue test. Plasma testing identified about half of the patients with EGFR mutations, compared to tissue testing (a sensitivity of 46%).
The tests in this study were not performed in specially selected central labs, but in local labs that are used for daily clinical routine. “This is important, because it does reflect the clinical reality and not a ‘virtual’ trial reality,” Reck said.
“The results mean that for patients who do not have accessible tumour tissue, plasma testing for EGFR mutation turns out to be an attractive option to offer these patients adequate targeted treatment,” Reck added.
Commenting on the study, Dr Rafael Rosell, from the Catalan Institute of Oncology, Barcelona, Spain, expert on the ESMO Faculty on Lung cancer, said: “Cell-free DNA detected in the bloodstream of cancer patients represents an excellent tool to examine genetic alterations that are usually found through tumour tissue testing. This represents one of the most astonishing phenomena in biology.”
“The results of this study validate that the presence of EGFR mutations in circulating DNA from plasma or serum (fractions obtained from whole blood) can be detected in around half of the patients.”
Already, since this study was performed, improvement of techniques have seen the sensitivity of tests for EGFR mutations in circulating tumour DNA increase further, Rosell noted.
“This work paves the way for further studies and expands the routine use of examining mutations such as EGFR mutations as part of cancer patient care,” Rosell said.
European Society for Medical Oncology
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Researchers from Queen Mary University of London have uncovered a genetic defect which causes the life-threatening condition ‘dyskeratosis congenita’ (DC) – a rare genetic form of bone marrow failure.
The researchers used the latest genetic sequencing methods to study 31 children with the disease and discovered a defect in the biological process known as deadenylation. This is the routine breakdown and recycling of the body’s messenger ribonucleic acid (mRNA) – the molecules which transcribe instructions from DNA to make proteins.
This is the first time a defect in the deadenylation process, controlled by the poly(A)-specific ribonuclease (PARN) gene, has been found to cause a genetic disease. Until now, scientists have believed that DC is caused by defective telomere maintenance (the caps of chromosomes that shorten with age). However, this research has shown that in some of these cases it’s the deadenylation deficiency which impacts the telomere maintenance, thereby causing the condition.
Dr Tom Vulliamy, Co-Senior Author at Queen Mary University of London, comments: “The discovery of this genetic cause of dyskeratosis congenita will immediately impact families with children suffering from this rare condition, as we’ll now be able to provide a definitive diagnosis – something we’ve been unable to do until now due to the complex nature of the disease. This will enable us to look after our patients more effectively, as well as offer genetic counselling and family planning advice.
“We are now recommending that all families who present with symptoms of this disease be screened for variants of the gene identified in this research.”
Dyskeratosis congenita is extremely rare and difficult to diagnose. It is characterised by a wide range of symptoms including changes in the skin, nails and mouth, neurological problems, along with a failure of the bone marrow to produce enough blood cells which leads to premature death.
Queen Mary University
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Testing for a DNA signature could predict which patients with myeloma – a cancer of immune cells in the blood and bone marrow – are likely to develop more serious disease, with a reduced chance of survival.
A team at The Institute of Cancer Research, London, found that cancer cells with the signature gain more DNA mutations than those without.
These mutations make the cancer more genetically complex, and more likely to evolve into treatment-resistant forms.
The study used genetic sequencing to analyse all of the genes of 463 patients with myeloma.
It searched for a genetic signature caused by a molecule called APOBEC, which edits DNA code in healthy immune cells to create the genetic diversity that allows them to adapt to threats from infection.
The molecule edits in a particular way, leaving a distinctive pattern that can be picked up by researchers through genetic sequencing.
The new study shows that APOBEC molecules become overactive in myeloma, or act on genes that they are not supposed to – leading to more advanced cancer. Eighteen of the patients analysed in the study had the APOBEC signature in their cells.
Along with the APOBEC signature, the researchers discovered that a number of other DNA and chromosome mutations were associated with more severe forms of the disease – including the common cancer gene, MYC.
Study leader Professor Gareth Morgan, who conducted the research as Professor of Haematology at the ICR, said:
“The treatment of myeloma has improved in recent years – but there are still a significant number of patients who succumb to the disease. Our research has identified, for the first time, several genetic features that indicate which patients are at high risk of developing more advanced cancer.
“In the future we hope to be able to use this information to test for patients most at risk, and be able to target specific treatment to their individual needs, bolstering their chance of survival.”
Eric Lowe, Chief Executive of Myeloma UK, said: “Adapting the current one-size-fits-all approach to treatment is critically important to ensure myeloma patients only receive treatment that is stratified to the specific nature of their disease and which has a high probability of working. We are grateful to the myeloma research team at the ICR for their hard work and dedication and are very proud that our programme grant is being used to fund such high-quality research, producing data that patients will benefit from in the clinic.’’
ICR
Institute of Cancer Research
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Researchers have generated a mouse with dysfunctional telomeres in the liver and, as a result, it developed cellular alterations present in human diseases such as hepatitis or cirrhosis
This study is the first to show that alterations in the functioning of telomeres lead to changes in the liver that are common to diseases such as hepatitis and cirrhosis, which are associated with an increased risk of liver cancer
This finding provides the basis for understanding the molecular origin of these diseases, as well as identifying new therapeutic strategies for their prevention and control
Telomeres are DNA regions at the ends of our chromosomes that protect the genetic data of cells, preventing mutations and alterations in the DNA that could potentially cause disease. Telomeres shorten throughout life in a process involving both genetic and environmental factors. Telomere dysfunction —alterations in the structure and/or functioning of telomeres— is one of the molecular mechanisms underlying a number of age-related diseases but, to date, little is known about its possible role in pathologies of the liver such as cirrhosis, hepatitis and liver cancer.
In a study Fabian Beier and Paula Martínez —from the Spanish National Cancer Research Centre´s (CNIO) Telomere and Telomerase Group led by Maria Blasco— have created a mouse model that recapitulates the origin of human diseases associated with long-term or chronic liver damage, such as hepatitis or cirrhosis of the liver which, in turn, can progress to liver cancer over time. This new mouse model reveals telomeric dysfunction as a potential factor in triggering these diseases.
In order to study the relationship between telomeres and liver damage, the researchers generated a mouse line deficient in TRF1 protein in the liver, thus leaving the telomeres in hepatic cells unprotected and compromising their function. TRF1 forms part of a protective complex of our telomeres called shelterin (from the word shelter), which protects our genetic material.
When researchers subjected the mice with TRF1 deficiency to chronic stress by administering the hepatotoxic agent CCl4 —responsible for liver toxicity— they observed that hepatic cells, in addition to containing multiple nuclei, also presented characteristics that are typical of patients with cirrhosis or hepatitis, such as an increase in cellular markers p21, cyclin D1 or PCNA.
‘These studies identify telomeres as a new molecular route implicated in the origin of liver diseases such as cirrhosis, hepatitis or liver cancer, as well as novel therapeutic approaches to prevent and combat them,’ concluded the researchers.
EASL
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Researchers lead collaborative charge to uncover genetic diversity of pancreatic cancer
, /in E-News /by 3wmediaA genetic analysis led by UT Southwestern Medical Center researchers suggests that most pancreatic cancers harbour genetic alterations that could be targeted by existing drugs, using their genetic features as a roadmap for treatment. The findings support a precision approach to treating pancreatic cancer, the fourth most deadly cancer for both men and women.
A comprehensive DNA sequencing of pancreatic cancer cases revealed not only a plethora of damaged genes, but potential diagnostic biomarkers that could help identify those with longer or shorter survival, and provide opportunity for new therapeutic interventions.
“We identified a wealth of genetic diversity, including multiple mutated genes that were previously unknown to pancreatic cancer − an important step in gaining a better understanding of this difficult and particularly deadly disease,” said lead author Dr. Agnieszka Witkiewicz, Associate Professor of Pathology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. “Importantly, the team was able to identify several genes that may be able to help us to predict outcomes in certain circumstances or serve as good candidates for therapeutic efforts.”
Researchers have long hoped that genetic analysis would provide insight into the biology of pancreatic cancer and define new targets for more effective treatment. Achieving this goal has been hampered by the technical difficulty of isolating pure cancer cells out of the tumour tissue that contains both tumour cells as well as normal cells. The new study overcame this limitation by selectively dissecting cancer cells from pieces of tumour tissue. This method was applied to specifically determine the genetic features of 109 different tumours.
The data showed that the genetic architecture of pancreatic cancer is complex, and each patient’s tumour was found to be unique. The genetic features illuminated ways in which the disease arises, defined events associated with survival, and yielded potential targets for therapeutic intervention.
“While we suspect that genetics can be used as the basis of targeted treatments, this point will only be proven through extensive research and clinical studies, hopefully leading to improved outcomes for patients,” said senior author Dr. Erik Knudsen, Professor of Pathology, and member of the Simmons Cancer Center who holds the Dr. Charles T. Ashworth Professorship in Pathology. “I am considerably more optimistic of the utility of a genetically targeted therapy for pancreatic cancer today than when we began this work.”
Pancreatic cancer is particularly difficult to treat, and is often diagnosed at a late stage when it is no longer amenable to surgical removal. Chemotherapy has a modest effect, and unfortunately the disease progresses in the vast majority of cases. Therefore, new therapeutic regimens are urgently needed. UT Southwestern Medical Center
Advances in understanding of eating disorders
, /in E-News /by 3wmediaBuilding on their discovery of a gene linked to eating disorders in humans, a team of researchers at the University of Iowa has now shown that loss of the gene in mice leads to several behavioural abnormalities that resemble behaviours seen in people with anorexia nervosa.
The team, led by Michael Lutter, MD, PhD, assistant professor of psychiatry in the UI Carver College of Medicine, found that mice that lack the oestrogen-related receptor alpha (ESRRA) gene are less motivated to seek out high-fat food when they are hungry and have abnormal social interactions. The effect was stronger in female mice, which also showed increased obsessive-compulsive-like behaviours.
The study also shows that ESRRA levels are controlled by energy status in the mice. Restricting calorie intake to 60 percent of normal over several days significantly increased levels of ESRRA in the brains of normal mice.
“Decreased calorie intake usually motivates animals, including humans, to seek out high-calorie food. These findings suggest that loss of ESRRA activity may disrupt that response,” Lutter says.
Anorexia nervosa and bulimia nervosa are common and severe mental illnesses. Lutter notes that although 50 to 70 percent of the risk of getting an eating disorder is inherited, identifying the genes that mediate this risk has proven difficult. Learn more about the treatment of eating disorders at UI Hospitals and Clinics.
ESRRA is a transcription factor—a gene that turns on other genes. Lutter and his colleagues previously found that a mutation that reduces ESRRA activity is associated with an increased risk for eating disorders in human patients. Although ESRRA is expressed in many brain regions that are disrupted in anorexia, almost nothing was known about its function in the brain. In the new study Lutter’s team manipulated ESRRA in mice to investigate the gene’s role in behaviour. University of Iowa Hospitals and Clinics
New technology for early detection of stomach cancer
, /in E-News /by 3wmediaInnovative gastric cancer-detection technology can be used for the early detection of stomach cancer and for identifying persons at risk for developing the disease. The new detection method, based on breath analysis, has significant advantages over the existing detection technology.
Gastric cancer is one of the most lethal forms of cancer and in most cases, its diagnosis involves an endoscopy (the insertion of a tube into the oesophagus, requiring that the patient fast and receive an intravenous sedative). Treatment is aggressive chemotherapy, radiation and the full or partial removal of the stomach. The disease develops in a series of well-defined steps, but there’s currently no effective, reliable, and non-invasive screening test for picking up these changes early on. Thus, many people succumb to stomach cancer only because it was not diagnosed in time.
The new technology, developed by Prof. Hossam Haick of the Technion Faculty of Chemical Engineering, can be used to detect premalignant lesions at the earliest stage, when healthy cells start becoming cancerous.
The research, published as part of the doctoral thesis of Mr. Haitham Amal, was conducted in conjunction with a Latvian research group headed by Prof. Marcis Leja, based on the largest population sample ever in a trial of this type. 484 people participated in the trial, 99 of whom had already been diagnosed with stomach cancer. All the participants were tested for Helicobacter pylori, a bacterium known to increase the risk for stomach cancer, and two breath samples were taken from each person.
The first sample from each participant was analysed using the GCMS technique, which measures volatile organic substances in exhaled breath. The researchers noted that GCMS technology cannot be used to detect stomach cancer because the testing is very expensive and requires lengthy processing times and considerable expertise to operate the equipment.
The second breath sample was tested using nanoarray analysis, the unique technology developed by Prof. Haick, combined with a pattern recognition algorithm.
The findings:
Based on the concentrations of 8 specific substances (out of 130) in the oral cavity, the new technology can distinguish between three groups: gastric cancer patients, persons who have precancerous stomach lesions, and healthy individuals.
The new technology accurately distinguishes between the various pre-malignant stages.
The new technology can be used to identify persons at risk for developing gastric cancer.
The diagnosis is accurate, regardless of other factors such as age, sex, smoking habits, alcohol consumption and the use of anti-oxidant drugs.
In short, the nano-array analysis method developed by Prof. Haick is accurate, sensitive technology that provides a simple and inexpensive alternative to existing tests (such as GCMS). This new technology offers early, effective detection of persons at risk for developing stomach cancer, without unnecessary invasive tests (endoscopy). In order to assess the accuracy and effectiveness of the new, a wide-scale clinical trial is currently under way in Europe, with thousands of participants who have cancerous or pre-cancerous tumours. Technion
Genomics tool could help predict tumour aggressiveness, treatment outcomes
, /in E-News /by 3wmediaA new method for measuring genetic variability within a tumour might one day help doctors identify patients with aggressive cancers that are more likely to resist therapy, according to a study led by researchers now at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).
Researchers used a new scoring method they developed called MATH (mutant-allele tumour heterogeneity) to measure the genetic variability among cancer cells within tumours from 305 patients with head and neck cancer. High MATH scores corresponded to tumours with many differences among the gene mutations present in different cancer cells.
Cancers that showed high genetic variability – called ‘intra-tumour heterogeneity’ – correlated with lower patient survival. If prospective studies verify the findings, MATH scores could help identify the most effective treatment for patients and predict a patient’s prognosis.
Researchers have long hypothesized that multiple sub-populations of mutated cells within a single cancer lead to worse clinical outcomes; however, oncologists do not use tumour heterogeneity to guide clinical care decisions or assess disease prognosis because there is no single, easy-to-implement method of doing so in clinical practice.
To address this need, James Rocco, MD, PhD, and his colleagues developed MATH to make it easier for doctors to measure genetic variability in patients’ tumours and to help guide treatment decisions.
The new findings confirm that high genetic variability with a patient’s tumour is related to increased mortality in head and neck squamous cell carcinoma.
‘Genetic variability within tumours is likely why people fail treatment,’ says Rocco, Professor and John and Mary Alford Chair of Head and Neck Surgery and Director of the OSUCCC – James Division of Head and Neck Oncologic Surgery. ‘In patients who have high heterogeneity tumours it is likely that there are several clusters of underlying mutations – in the same tumour – driving the cancer. So their tumours are likely to have some cells that are already resistant to any particular therapy.’
For the current study, Rocco and his team used the MATH tool to analyse retrospective data from 305 head and neck squamous cell carcinoma patients from The Cancer Genome Atlas (TCGA). This National Institutes of Health repository of publicly available data was launched in 2006 as a pilot project and now includes samples from more than 11,000 patients across 33 tumour types. The MATH score was calculated from data obtained by TCGA with a genome sequencing technique called whole-exome sequencing.
Researchers confirmed that high intra-tumour heterogeneity was related to increased mortality in this sub segment of patients. Each 10 percent increase in MATH score corresponded to an 8.8 percent increased likelihood of death.
The relationship between MATH score and mortality was not dependent on HPV (human papilloma virus) status or other molecular characteristics of the tumour.
‘Our retrospective analysis showed that patients with high heterogeneity tumours were more than twice as likely to die compared to patients with low heterogeneity tumors,’ says Rocco. ‘This type of information could refine the dialogue about how we tackle cancer by helping us predict a patient’s treatment success and justify clinical decisions based on the unique makeup of a patient’s tumor.’ EurekAlert
Mouth, as well as gut, could hold key to liver disease flare-ups
, /in E-News /by 3wmediaIn a recent study, Virginia Commonwealth University School of Medicine researchers predicted which cirrhosis patients would suffer inflammations and require hospitalization by analysing their saliva, revealing a new target for research into a disease that accounts for more than 30,000 deaths in the United States each year.
The findings could trigger a change in the way researchers study chronic liver disease and associated microbiota, the network of tiny organisms in the human body such as bacteria and fungi that can either bolster an immune system or weaken it.
The breakdown of defences in the mucosa of the gut has long been a signal of inflammation in those with cirrhosis, which sees healthy liver tissue replaced by scar tissue.
The recent findings suggest that another part of the body also can produce warning signs.
“It has been believed that most of the pathogenesis of cirrhosis starts in the gut, which is what makes this discovery so fascinating,” said Jasmohan S. Bajaj, M.D., associate professor of hepatology in the VCU School of Medicine and Hunter Holmes McGuire Veterans Affairs Medical Center.“The fact that saliva, along with fluid in the gut, can be an indicator of inflammation tells us that we need to further explore the oral cavity and its connections to liver disease.”
The paper describes a study of more than 100 cirrhosis patients from VCU and VA Medical Center, 38 of which had to be hospitalized within 90 days because of flare-ups. Researchers found that the ratio of good-to-bad microbes was similar in the saliva as in the stool of these patients who required hospitalization.
Another part of the same study looked at an additional group of more than 80 people with and without cirrhosis. Those with cirrhosis had impaired salivary defenses, mirroring the immune deficiencies that take place in the gut.
“The data suggest that there may be a change in the overall mucosal-immune interface in cirrhosis patients, allowing a more toxic microbiota to emerge in both the gut and oral cavity,” said Phillip B. Hylemon, Ph.D., professor of microbiology and immunology in the VCU School of Medicine and co-author of the paper.
In addition to using oral microbiota to predict the disease status of cirrhosis patients, Hylemon said the new evidence could provide a useful tool for testing treatment protocols for patients with cirrhosis or other diseases driven by inflammation. Virginia Commonwealth University Scool of Medicine
Gene variant linked to smoking longer, getting lung cancer sooner
, /in E-News /by 3wmediaSmokers with a specific genetic variation are more likely to keep smoking longer than those who don’t have the gene variant, new research indicates. They’re also more likely to be diagnosed with lung cancer at a younger age.
Researchers at Washington University School of Medicine in St. Louis led an analysis of 24 studies involving more than 29,000 smokers of European ancestry and found that smokers with a particular variation in a nicotine receptor gene were more likely to continue smoking for four years after those without the variant had quit. Those with the genetic variant also were more likely to be diagnosed with lung cancer four years earlier than those without the variation in the CHRNA5 gene.
The findings may result in changes to efforts to screen patients for lung cancer.
“People with the risk variant average a four-year delay in the age at which they quit smoking,” said first author Li-Shiun Chen, MD. “Instead of quitting at age 52, which was the average age when study participants with a normal gene stopped smoking, people with the genetic variant quit at age 56.”
Chen said those with the gene variant also tend to inhale more deeply when they smoke. That combination of genes and behaviour contributes to the development of lung cancer earlier in life.
“They are likely to be diagnosed four years earlier,” she said. “In those with lung cancer, the average smoker without the gene variant is diagnosed at age 65. Those with the greater genetic risk tend to be diagnosed at 61.”
Chen said the presence of the gene variation has important clinical implications. Smokers who have the gene variant could undergo lung cancer screening at a younger age, she said. In addition, previous work from Chen and senior investigator Laura Jean Bierut, MD, shows that those with the gene variant are more likely to respond to medications that help people quit smoking, so knowing more about a smoker’s genetic makeup could help guide that individual’s therapy.
“The same people with this high-risk gene are more likely to respond to smoking-cessation medications, such as nicotine-replacement patches, lozenges or gum,” Chen said. “Although it’s clear the gene increases the chances a person will develop lung cancer at a younger age, it also is clear that the risk can be reversed with treatment.” Washington University in St Louis
Circulating tumour DNA in blood a valid option for EGFR testing in patients who do not have accessible tumour tissue
, /in E-News /by 3wmediaCancer DNA circulating in the bloodstream of lung cancer patients can provide doctors with vital mutation information that can help optimise treatment when tumour tissue is not available, an international group of researchers has reported at the European Lung Cancer Conference (ELCC) in Geneva, Switzerland.
The results have important implications for the use of cancer therapies that target specific cancer mutations, explains Dr Martin Reck from the Department of Thoracic Oncology at Lung Clinic Grosshansdorf, Germany, who presented the findings at the conference.
Testing for the presence of these mutations in the tumour itself is not always possible, however studies have suggested that DNA from the tumour that circulates in the bloodstream of patients may provide similar information.
The large international ASSESS study aimed to compare the ability of blood testing to detect EGFR mutations with the more standard method of testing the tumour itself.
“We were really asking a question on behalf of patients,” Reck said: “Is there a valid test that can identify an EGFR mutation and give me the opportunity for superior treatment, even if my lung tumour is not accessible for bronchoscopy or CT-guided biopsy? And, are the results of this blood test in agreement with the results of the ‘gold-standard’ tissue test?”
Overall, the study included 1162 matched tissue and blood samples. Comparison of the outcomes of EGFR testing in the two techniques showed an 89% rate of agreement between the blood test and tissue test. Plasma testing identified about half of the patients with EGFR mutations, compared to tissue testing (a sensitivity of 46%).
The tests in this study were not performed in specially selected central labs, but in local labs that are used for daily clinical routine. “This is important, because it does reflect the clinical reality and not a ‘virtual’ trial reality,” Reck said.
“The results mean that for patients who do not have accessible tumour tissue, plasma testing for EGFR mutation turns out to be an attractive option to offer these patients adequate targeted treatment,” Reck added.
Commenting on the study, Dr Rafael Rosell, from the Catalan Institute of Oncology, Barcelona, Spain, expert on the ESMO Faculty on Lung cancer, said: “Cell-free DNA detected in the bloodstream of cancer patients represents an excellent tool to examine genetic alterations that are usually found through tumour tissue testing. This represents one of the most astonishing phenomena in biology.”
“The results of this study validate that the presence of EGFR mutations in circulating DNA from plasma or serum (fractions obtained from whole blood) can be detected in around half of the patients.”
Already, since this study was performed, improvement of techniques have seen the sensitivity of tests for EGFR mutations in circulating tumour DNA increase further, Rosell noted.
“This work paves the way for further studies and expands the routine use of examining mutations such as EGFR mutations as part of cancer patient care,” Rosell said. European Society for Medical Oncology
Scientists discover genetic cause of deadly rare disease ‘dyskeratosis congenita’
, /in E-News /by 3wmediaResearchers from Queen Mary University of London have uncovered a genetic defect which causes the life-threatening condition ‘dyskeratosis congenita’ (DC) – a rare genetic form of bone marrow failure.
The researchers used the latest genetic sequencing methods to study 31 children with the disease and discovered a defect in the biological process known as deadenylation. This is the routine breakdown and recycling of the body’s messenger ribonucleic acid (mRNA) – the molecules which transcribe instructions from DNA to make proteins.
This is the first time a defect in the deadenylation process, controlled by the poly(A)-specific ribonuclease (PARN) gene, has been found to cause a genetic disease. Until now, scientists have believed that DC is caused by defective telomere maintenance (the caps of chromosomes that shorten with age). However, this research has shown that in some of these cases it’s the deadenylation deficiency which impacts the telomere maintenance, thereby causing the condition.
Dr Tom Vulliamy, Co-Senior Author at Queen Mary University of London, comments: “The discovery of this genetic cause of dyskeratosis congenita will immediately impact families with children suffering from this rare condition, as we’ll now be able to provide a definitive diagnosis – something we’ve been unable to do until now due to the complex nature of the disease. This will enable us to look after our patients more effectively, as well as offer genetic counselling and family planning advice.
“We are now recommending that all families who present with symptoms of this disease be screened for variants of the gene identified in this research.”
Dyskeratosis congenita is extremely rare and difficult to diagnose. It is characterised by a wide range of symptoms including changes in the skin, nails and mouth, neurological problems, along with a failure of the bone marrow to produce enough blood cells which leads to premature death. Queen Mary University
Genetic ‘signature’ points to poor blood cancer outcome
, /in E-News /by 3wmediaTesting for a DNA signature could predict which patients with myeloma – a cancer of immune cells in the blood and bone marrow – are likely to develop more serious disease, with a reduced chance of survival.
A team at The Institute of Cancer Research, London, found that cancer cells with the signature gain more DNA mutations than those without.
These mutations make the cancer more genetically complex, and more likely to evolve into treatment-resistant forms.
The study used genetic sequencing to analyse all of the genes of 463 patients with myeloma.
It searched for a genetic signature caused by a molecule called APOBEC, which edits DNA code in healthy immune cells to create the genetic diversity that allows them to adapt to threats from infection.
The molecule edits in a particular way, leaving a distinctive pattern that can be picked up by researchers through genetic sequencing.
The new study shows that APOBEC molecules become overactive in myeloma, or act on genes that they are not supposed to – leading to more advanced cancer. Eighteen of the patients analysed in the study had the APOBEC signature in their cells.
Along with the APOBEC signature, the researchers discovered that a number of other DNA and chromosome mutations were associated with more severe forms of the disease – including the common cancer gene, MYC.
Study leader Professor Gareth Morgan, who conducted the research as Professor of Haematology at the ICR, said:
“The treatment of myeloma has improved in recent years – but there are still a significant number of patients who succumb to the disease. Our research has identified, for the first time, several genetic features that indicate which patients are at high risk of developing more advanced cancer.
“In the future we hope to be able to use this information to test for patients most at risk, and be able to target specific treatment to their individual needs, bolstering their chance of survival.”
Eric Lowe, Chief Executive of Myeloma UK, said: “Adapting the current one-size-fits-all approach to treatment is critically important to ensure myeloma patients only receive treatment that is stratified to the specific nature of their disease and which has a high probability of working. We are grateful to the myeloma research team at the ICR for their hard work and dedication and are very proud that our programme grant is being used to fund such high-quality research, producing data that patients will benefit from in the clinic.’’
ICR Institute of Cancer Research
CNIO Researchers link telomeres to the origins of liver diseases
, /in E-News /by 3wmediaResearchers have generated a mouse with dysfunctional telomeres in the liver and, as a result, it developed cellular alterations present in human diseases such as hepatitis or cirrhosis
This study is the first to show that alterations in the functioning of telomeres lead to changes in the liver that are common to diseases such as hepatitis and cirrhosis, which are associated with an increased risk of liver cancer
This finding provides the basis for understanding the molecular origin of these diseases, as well as identifying new therapeutic strategies for their prevention and control
Telomeres are DNA regions at the ends of our chromosomes that protect the genetic data of cells, preventing mutations and alterations in the DNA that could potentially cause disease. Telomeres shorten throughout life in a process involving both genetic and environmental factors. Telomere dysfunction —alterations in the structure and/or functioning of telomeres— is one of the molecular mechanisms underlying a number of age-related diseases but, to date, little is known about its possible role in pathologies of the liver such as cirrhosis, hepatitis and liver cancer.
In a study Fabian Beier and Paula Martínez —from the Spanish National Cancer Research Centre´s (CNIO) Telomere and Telomerase Group led by Maria Blasco— have created a mouse model that recapitulates the origin of human diseases associated with long-term or chronic liver damage, such as hepatitis or cirrhosis of the liver which, in turn, can progress to liver cancer over time. This new mouse model reveals telomeric dysfunction as a potential factor in triggering these diseases.
In order to study the relationship between telomeres and liver damage, the researchers generated a mouse line deficient in TRF1 protein in the liver, thus leaving the telomeres in hepatic cells unprotected and compromising their function. TRF1 forms part of a protective complex of our telomeres called shelterin (from the word shelter), which protects our genetic material.
When researchers subjected the mice with TRF1 deficiency to chronic stress by administering the hepatotoxic agent CCl4 —responsible for liver toxicity— they observed that hepatic cells, in addition to containing multiple nuclei, also presented characteristics that are typical of patients with cirrhosis or hepatitis, such as an increase in cellular markers p21, cyclin D1 or PCNA.
‘These studies identify telomeres as a new molecular route implicated in the origin of liver diseases such as cirrhosis, hepatitis or liver cancer, as well as novel therapeutic approaches to prevent and combat them,’ concluded the researchers. EASL