An international research team led by the Research Institute of the McGill University Health Centre (RI MUHC) has made a major genetic breakthrough that could change the way pediatric cancers are treated in the future. The researchers identified two genetic mutations responsible for up to 40 per cent of glioblastomas in children -- a fatal cancer of the brain that is unresponsive to chemo and radiotherapy treatment. The mutations were found to be involved in DNA regulation, which could explain the resistance to traditional treatments, and may have significant implications on the treatment of other cancers.
The study was published this week in the journal Nature.
Using the knowledge and advanced technology of the team from the McGill University and Génome Québec Innovation Centre, the researchers identified two mutations in an important gene known as the histone H3.3. This gene, one of the guardians of our genetic heritage, is key in modulating the expression of our genes. "These mutations prevent the cells from differentiating normally and help protect the genetic information of the tumor, making it less sensitive to radiotherapy and chemotherapy," says Dr. Nada Jabado, hematologist-oncologist at The Montreal Children's Hospital of the McGill University Health Centre (MUHC) and principal investigator of the study.
"This research helps explain the ineffectiveness of conventional treatments against cancer in children and adolescents -- we've been failing to hit the right spot," says Dr. Jabado, who is also an Associate Professor of Pediatrics at McGill University. "It is clear now that glioblastoma in children is due to different molecular mechanisms than those in adults, and should not be treated in the same way. Importantly, we now know where to start focusing our efforts and treatments instead of working in the dark."
Inappropriate regulation of this gene has been observed in other cancers such as colon, pancreatic, lymphoma, leukemia and pancreatic neuroendocrine cancer, and future research could therefore reveal improved treatments for these diseases. "What is significant here is that for the first time in humans we have identified a mutation in one of the most important genes that regulates and protects our genetic information. This is the irrefutable proof that our genome, if modified, can lead to cancer and probably other diseases. What genomics has shown us today is only the beginning," says Dr. Jabado.
"Génome Québec is proud to have contributed to a project whose results will make a significant impact on the treatment of pediatric glioblastoma," underlines Marc Le Page, President and CEO of Génome Québec. "The outstanding contribution of experts in genomics and new sequencing technologies, made by the McGill University and Génome Québec Innovation Centre and as part of Dr. Jabado's project, is further proof that genomics has become essential for development and innovation in medical research. I wish to acknowledge the excellence of the teams involved in this study and the model of interdisciplinary collaboration that was implemented."
"Personalized medicine has amazing potential for many areas of health care, including infection, rare diseases and cancer. Researchers, like this team, play a vital role in translating discoveries into improved patient care," says Dr. Morag Park, Scientific Director of the CIHR Institute of Cancer Research. "Through research advancements like this, there is now greater emphasis on using genetic information to make medical decisions. We congratulate Dr. Jabado and her team on these results."
Brain tumours are the primary cause of death for children with cancer in Europe and North America. The diagnosis of glioblastoma in a child or adolescent remains a death sentence and about 200 children in Canada die every year of this cancer. Most children will die within the two years of their diagnosis regardless of treatment.
This work was supported by the Cole Foundation, and was funded in part by Genome Canada and the Canadian Institute for Health Research (CIHR) with co-funding from Genome BC, Génome Québec, CIHR-ICR (Institute for Cancer Research) and C17, through the Genome Canada/CIHR joint ATID Competition (project title: The Canadian Paediatric Cancer Genome Consortium: Translating next generation sequencing technologies into improved therapies for high-risk childhood cancer.
Tuesday, January 31, 2012
Cutting off the oxygen supply to serious diseases
A new family of proteins which regulate the human body’s ‘hypoxic response’ to low levels of oxygen has been discovered by scientists at Barts Cancer Institute at Queen Mary, University of London and The University of Nottingham.
The discovery has been published in the international journal Nature Cell Biology. It marks a significant step towards understanding the complex processes involved in the hypoxic response which, when it malfunctions, can cause and affect the progress of many types of serious disease, including cancer.
The researchers have uncovered a previously unknown level of hypoxic regulation at a molecular level in human cells which could provide a novel pathway for the development of new drug therapeutics to fight disease. The cutting-edge work was funded by the Biotechnology and Biological Sciences Research Council (BBSRC).
Proteins are biochemical compounds which carry out specific duties within the living cell. Every cell in our body has the ability to recognise and respond to changes in the availability of oxygen. The best example of this is when we climb to high altitudes where the air contains less oxygen. The cells recognise the decrease in oxygen via the bloodstream and are able to react, using the ‘hypoxic response’, to produce a protein called EPO. This protein in turn stimulates the body to produce more red blood cells to absorb as much of the reduced levels of oxygen as possible.
This response is essential for a normal healthy physiology but when the hypoxic response in cells malfunctions, diseases like cancer can develop and spread. Cancer cells have a faulty hypoxic response which means that as the cells multiply they highjack the response to create their own rogue blood supply. In this way the cells can form large tumours. The new blood supply also helps the cancer cells spread to other parts of the body, called ‘metastasis’, which is how ultimately cancer kills patients.
The scientists have identified a new family of hypoxic regulator proteins called ‘LIM domain containing proteins’ which function as molecular scaffolds or ‘adapters’ bringing together or bridging two key enzymes in the hypoxic response pathway, namely PHD2 and VHL. Both of these are involved in down-regulating the master regulator protein called Hypoxia-inducible factors (HIF1). The research has shown that loss of LIMD1 breaks down the bridge it creates between PHD2 and VHL and this then enables the master regulator to function out of control and thus contribute to cancer formation.
Molecular Oncologist, Dr Tyson Sharp, who carried out research for the project at The University of Nottingham’s School of Biomedical Sciences, said: “The results from this research represent a significant advancement in our understanding of precisely how the hypoxic response works. It will help researchers develop better drugs to fight cancer and also other human diseases that are caused by low levels of oxygen within our body such as anaemia, myocardial infarction (heart attack), stroke and peripheral arterial disease.
Further work in this fascinating area is now continuing at Barts Cancer Institute at Queen Mary University of London and will form the basis of a whole new additional research theme for my group.”
The discovery has been published in the international journal Nature Cell Biology. It marks a significant step towards understanding the complex processes involved in the hypoxic response which, when it malfunctions, can cause and affect the progress of many types of serious disease, including cancer.
The researchers have uncovered a previously unknown level of hypoxic regulation at a molecular level in human cells which could provide a novel pathway for the development of new drug therapeutics to fight disease. The cutting-edge work was funded by the Biotechnology and Biological Sciences Research Council (BBSRC).
Proteins are biochemical compounds which carry out specific duties within the living cell. Every cell in our body has the ability to recognise and respond to changes in the availability of oxygen. The best example of this is when we climb to high altitudes where the air contains less oxygen. The cells recognise the decrease in oxygen via the bloodstream and are able to react, using the ‘hypoxic response’, to produce a protein called EPO. This protein in turn stimulates the body to produce more red blood cells to absorb as much of the reduced levels of oxygen as possible.
This response is essential for a normal healthy physiology but when the hypoxic response in cells malfunctions, diseases like cancer can develop and spread. Cancer cells have a faulty hypoxic response which means that as the cells multiply they highjack the response to create their own rogue blood supply. In this way the cells can form large tumours. The new blood supply also helps the cancer cells spread to other parts of the body, called ‘metastasis’, which is how ultimately cancer kills patients.
The scientists have identified a new family of hypoxic regulator proteins called ‘LIM domain containing proteins’ which function as molecular scaffolds or ‘adapters’ bringing together or bridging two key enzymes in the hypoxic response pathway, namely PHD2 and VHL. Both of these are involved in down-regulating the master regulator protein called Hypoxia-inducible factors (HIF1). The research has shown that loss of LIMD1 breaks down the bridge it creates between PHD2 and VHL and this then enables the master regulator to function out of control and thus contribute to cancer formation.
Molecular Oncologist, Dr Tyson Sharp, who carried out research for the project at The University of Nottingham’s School of Biomedical Sciences, said: “The results from this research represent a significant advancement in our understanding of precisely how the hypoxic response works. It will help researchers develop better drugs to fight cancer and also other human diseases that are caused by low levels of oxygen within our body such as anaemia, myocardial infarction (heart attack), stroke and peripheral arterial disease.
Further work in this fascinating area is now continuing at Barts Cancer Institute at Queen Mary University of London and will form the basis of a whole new additional research theme for my group.”
Study finds that inherited risk factors for childhood leukemia are more common in Hispanic patients
Hispanic children are more likely than those from other racial and ethnic backgrounds to be diagnosed with acute lymphoblastic leukemia (ALL) and are more likely to die of their disease. Work led by St. Jude Children's Research Hospital scientists has pinpointed genetic factors behind the grim statistics.
Researchers studying a gene called ARID5B linked eight common variants of the gene to an increased risk of not only developing pediatric ALL but of having the cancer return after treatment. Two more ARID5B variants were tied to higher odds of developing the disease. Investigators found that Hispanic children were up to twice as likely as their white counterparts to inherit a high risk-version of ARID5B.
"For years we have known about ethnic and racial disparities in ALL risk and outcome, but the biology behind it has been elusive. Therefore, it is truly exciting to be able to not only pin down the biological basis but to find that the same gene might be responsible for both differences. Children who inherit high-risk versions of ARID5B are more likely to develop ALL in the first place and then more likely to fail therapy," said Jun Yang, Ph.D., an assistant member of the St. Jude Department of Pharmaceutical Sciences and the paper's corresponding author.
The work was done in collaboration with the Children's Oncology Group (COG), a U.S. based research cooperative study group focused on childhood cancer research and clinical trials. The study appears in the January 30 online edition of the Journal of Clinical Oncology.
Multiple factors contribute to cancer development, and inheriting a high-risk version of ARID5B is not enough to cause the disease, Yang said. These findings set the stage for exciting research in understanding how genetic, environmental and other factors combine in ALL, especially in the context of racial and ethnic disparity, he said.
"These and other genomic studies suggest we are poised to finally make significant progress in eliminating racial disparities in this catastrophic disease," Yang said. Additional work is needed to translate these findings into new clinical tools, he added.
Each year ALL is found in about 3,000 U.S. children, making it the most common childhood cancer. The incidence varies by self-declared race and ethnicity with rates for Hispanic individuals 50 percent higher than for non-Hispanic white individuals. For this study, researchers used genetic variations rather than individual self-report to define ancestry. White children were defined as having greater than 95 percent European ancestry and Hispanics children as having greater than 10 percent Native American ancestry.
Although the work of St. Jude researchers and others is helping to close the survival gap, Hispanic children are still less likely than children from other racial or ethnic backgrounds to be alive five years after diagnosis.
This study builds on the earlier St. Jude research that linked different versions of the ARID5B gene to ALL risk.
St. Jude and COG investigators partnered to see if variations in the ARID5B gene help to explain differences in either the incidence or the outcome of ALL in white and Hispanic patients. ARID5B belongs to a family of genes called transcription factors. They play a role in the normal development of white blood cells, which are targeted in ALL. Evidence suggests the gene also influences how methotrexate, a key anti-leukemia drug, is metabolized.
To find ARID5B variants related to ALL, the study compared the gene in 330 Hispanic children with ALL and 541 Hispanic individuals without ALL. Researchers also checked ARID5B in 978 white ALL patients and 1,046 white individuals without the cancer.
Although the high-risk versions of ARID5B were found in both white and Hispanic patients, those variants were 1.5 to two times more common in Hispanic children than in white children.
Individuals inherit two copies of every gene, one from each parent. Children with one high-risk version of ARID5B were up to 80 percent more likely to develop ALL than others. Inheriting two copies of a high-risk version of the gene translated into a 3.6-fold increased ALL risk.
Researchers also found evidence linking ARID5B variants to relapse risk in 1,605 pediatric ALL patients enrolled in COG studies. Yang and his colleagues previously linked that level of Native American ancestry to a higher relapse risk in Hispanic ALL patients. Patients in this study who inherited a high-risk version of ARID5B were 50 percent more likely to relapse than other patients. They were also more likely to die of their cancer.
The study's first author is Heng Xu of St. Jude. Other authors are Cheng Cheng, Deqing Pei, Yiping Fan, Wenjian Yang, Geoff Neale, William E. Evans, Ching-Hon Pui, and Mary Relling, all of St. Jude; Meenakshi Devidas, University of Florida, Gainesville; Paul Scheet, University of Texas MD Anderson Cancer Center; Esteban Gonzalez Burchard, Dara Torgerson, Celeste Eng and Mignon Loh, all of University of California, San Francisco; Michael Dean, National Cancer Institute; Federico Antillon, Unidad Nacional de Oncologia Pediatrica, Guatemala; Naomi Winick, University of Texas Southwestern Medical Center; Paul Martin, Duke University; Cheryl Willman, University of New Mexico; Bruce Camitta, Medical College of Wisconsin; Gregory Reaman, George Washington University, Children's National Medical Center; William Carroll, New York University; and Stephen Hunger, University of Colorado School of Medicine and Children's Hospital Colorado.
Yang was supported by the American Society of Hematology Scholar Award and the Alex Lemonade Stand Foundation for Childhood Cancer Young Investigator Award. The work was supported in part by the National Institutes of Health, the Jeffrey Pride Foundation, CureSearch and ALSAC.
Researchers studying a gene called ARID5B linked eight common variants of the gene to an increased risk of not only developing pediatric ALL but of having the cancer return after treatment. Two more ARID5B variants were tied to higher odds of developing the disease. Investigators found that Hispanic children were up to twice as likely as their white counterparts to inherit a high risk-version of ARID5B.
"For years we have known about ethnic and racial disparities in ALL risk and outcome, but the biology behind it has been elusive. Therefore, it is truly exciting to be able to not only pin down the biological basis but to find that the same gene might be responsible for both differences. Children who inherit high-risk versions of ARID5B are more likely to develop ALL in the first place and then more likely to fail therapy," said Jun Yang, Ph.D., an assistant member of the St. Jude Department of Pharmaceutical Sciences and the paper's corresponding author.
The work was done in collaboration with the Children's Oncology Group (COG), a U.S. based research cooperative study group focused on childhood cancer research and clinical trials. The study appears in the January 30 online edition of the Journal of Clinical Oncology.
Multiple factors contribute to cancer development, and inheriting a high-risk version of ARID5B is not enough to cause the disease, Yang said. These findings set the stage for exciting research in understanding how genetic, environmental and other factors combine in ALL, especially in the context of racial and ethnic disparity, he said.
"These and other genomic studies suggest we are poised to finally make significant progress in eliminating racial disparities in this catastrophic disease," Yang said. Additional work is needed to translate these findings into new clinical tools, he added.
Each year ALL is found in about 3,000 U.S. children, making it the most common childhood cancer. The incidence varies by self-declared race and ethnicity with rates for Hispanic individuals 50 percent higher than for non-Hispanic white individuals. For this study, researchers used genetic variations rather than individual self-report to define ancestry. White children were defined as having greater than 95 percent European ancestry and Hispanics children as having greater than 10 percent Native American ancestry.
Although the work of St. Jude researchers and others is helping to close the survival gap, Hispanic children are still less likely than children from other racial or ethnic backgrounds to be alive five years after diagnosis.
This study builds on the earlier St. Jude research that linked different versions of the ARID5B gene to ALL risk.
St. Jude and COG investigators partnered to see if variations in the ARID5B gene help to explain differences in either the incidence or the outcome of ALL in white and Hispanic patients. ARID5B belongs to a family of genes called transcription factors. They play a role in the normal development of white blood cells, which are targeted in ALL. Evidence suggests the gene also influences how methotrexate, a key anti-leukemia drug, is metabolized.
To find ARID5B variants related to ALL, the study compared the gene in 330 Hispanic children with ALL and 541 Hispanic individuals without ALL. Researchers also checked ARID5B in 978 white ALL patients and 1,046 white individuals without the cancer.
Although the high-risk versions of ARID5B were found in both white and Hispanic patients, those variants were 1.5 to two times more common in Hispanic children than in white children.
Individuals inherit two copies of every gene, one from each parent. Children with one high-risk version of ARID5B were up to 80 percent more likely to develop ALL than others. Inheriting two copies of a high-risk version of the gene translated into a 3.6-fold increased ALL risk.
Researchers also found evidence linking ARID5B variants to relapse risk in 1,605 pediatric ALL patients enrolled in COG studies. Yang and his colleagues previously linked that level of Native American ancestry to a higher relapse risk in Hispanic ALL patients. Patients in this study who inherited a high-risk version of ARID5B were 50 percent more likely to relapse than other patients. They were also more likely to die of their cancer.
The study's first author is Heng Xu of St. Jude. Other authors are Cheng Cheng, Deqing Pei, Yiping Fan, Wenjian Yang, Geoff Neale, William E. Evans, Ching-Hon Pui, and Mary Relling, all of St. Jude; Meenakshi Devidas, University of Florida, Gainesville; Paul Scheet, University of Texas MD Anderson Cancer Center; Esteban Gonzalez Burchard, Dara Torgerson, Celeste Eng and Mignon Loh, all of University of California, San Francisco; Michael Dean, National Cancer Institute; Federico Antillon, Unidad Nacional de Oncologia Pediatrica, Guatemala; Naomi Winick, University of Texas Southwestern Medical Center; Paul Martin, Duke University; Cheryl Willman, University of New Mexico; Bruce Camitta, Medical College of Wisconsin; Gregory Reaman, George Washington University, Children's National Medical Center; William Carroll, New York University; and Stephen Hunger, University of Colorado School of Medicine and Children's Hospital Colorado.
Yang was supported by the American Society of Hematology Scholar Award and the Alex Lemonade Stand Foundation for Childhood Cancer Young Investigator Award. The work was supported in part by the National Institutes of Health, the Jeffrey Pride Foundation, CureSearch and ALSAC.
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