Mammalian spermatogenesis is maintained by spermatogonial stem cells (SSCs). However, since evidentiary assays and unequivocal markers are still missing in non-human primates and man, the identity of primate SSCs is unknown. In contrast, in the mouse, germ cell transplantation studies functionally demonstrated the presence of SSCs. LIN28 is an RNA-binding pluripotent stem cell factor, which is also strongly expressed in undifferentiated mouse spermatogonia. By contrast, two recent reports indicated that LIN28 is completely absent from adult human testes. Here, we analysed LIN28 expression in marmoset monkey (Callithrix jacchus) and human testes during development and adulthood and compared it with the mouse. In the marmoset, LIN28 was strongly expressed in migratory PGCs and gonocytes. Strikingly, we found a rare LIN28-positive subpopulation of spermatogonia also in the adult marmoset testis. This was corroborated by western blotting and quantitative RT-PCR. Importantly, in contrast to previous publications, we found LIN28-positive spermatogonia also in normal adult human and additional adult non-human primate testes. Some seasonal breeders exhibit a degenerated (involuted) germinal epithelium during their non-breeding season consisting only of Sertoli cells and SSCs. The latter re-initiate spermatogenesis prior to the next breeding-season. Fully involuted testes from a seasonal hamster and NHP (Lemur catta) exhibited numerous LIN28-positive spermatogonia, indicating a SSC-identity of the labeled cells. We conclude that LIN28 is differentially expressed in mouse and non-human primate spermatogonia and might be a marker for a rare SSC population in non-human primates and man. Further characterization of the LIN28-positive population is required.
European Society of Human Reproduction and Embryology
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Researchers studying the genetic roots of the most common malignant childhood brain tumour have discovered missteps in three of the four subtypes of the cancer that involve genes already targeted for drug development.
The most significant gene alterations are linked to subtypes of medulloblastoma that currently have the best and worst prognosis. They were among 41 genes associated for the first time to medulloblastoma by the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project.
‘This study provides new direction for understanding what drives these tumours and uncovers totally unexpected new drug targets. There are drugs already in development against these targets aimed at treating adult cancers and other diseases,’ said Richard Gilbertson, M.D., Ph.D., St. Jude Comprehensive Cancer Center director. Gilbertson and Jinghui Zhang, Ph.D., an associate member of the St. Jude Department of Computational Biology, are the study’s corresponding authors.
The results mark progress toward more targeted therapies against medulloblastoma and other cancers. While better use of existing drugs and improved supportive care have helped push long-term survival rates for childhood cancer to about 80 percent, drug development efforts have largely stalled for more than two decades, particularly against pediatric brain tumours.
‘This study is a great example of the way whole-genome sequencing of cancer patients allows us to dig deep into the biology of certain tumors and catch a glimpse of their Achilles heel,’ said co-author Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis. ‘These results help us better understand the disease and, as a result, we will be able to more effectively diagnose and treat these kids.’
This study involved sequencing the complete normal and cancer genomes of 37 young patients with medulloblastoma, making it the largest such effort to date involving the cancer. Researchers then checked tumours from an additional 56 patients for the same alterations.
The findings are part of the Pediatric Cancer Genome Project, which launched in 2010 as a three-year effort to decipher the complete normal and tumour genomes of 600 young cancer patients with some of the most challenging tumours. The endeavour has already yielded important clues into the origin, spread and treatment response in childhood cancers of the blood, brain, eye and nervous system.
Medulloblastoma is diagnosed in about 400 U.S. children and adolescents annually. Their outcome varies widely based on the subtype they have. While nearly all patients with the wingless (WNT) subtype survive, just 60 percent of those with subtype 3 medulloblastoma are alive three years after diagnosis. WNT medulloblastoma is named for the pathway disrupted in the tumor subtype.
This study found a high percentage of patients with WNT-subtype medulloblastoma had mutations in the DDX3X gene. The investigators found evidence that mutated DDX3X is required to sustain the brain cells where WNT subtype tumours develop. The research also found evidence linking alterations in other genes, including CDH1 and PIK3CA, to the development and spread of the WNT subtype. ‘It is particularly exciting that these genes, or the pathways in which they work, are already the focus of drug development efforts. This opens up the possibility of using these drugs to treat medulloblastoma in new ways,’ said Giles Robinson, M.D., St. Jude Department of Oncology research associate and one of the study’s first authors.
Investigators demonstrated that subtype three and four medulloblastoma often had alterations in genes that impact cell maturation. The genes carry instructions for proteins that add or remove the chemical group methyl to the H3K27 protein. H3K27 is part of the chromatin structure that packages DNA to fit inside cells. That packaging helps determine if genes are switched on or off. The addition of methyl to H3K27 permits less specialised cells to keep dividing and blocks activity of genes that would prompt cells to stop dividing, differentiate and take on more specialised roles.
Some subgroup 3 and 4 tumours were characterised by a gain in EZH2, which adds methyl to H3K27. EZH2 is also associated with adult cancers and the focus of ongoing drug development. St. Jude has begun screening those and other compounds for evidence of effectiveness against medulloblastoma.
In other subtype 3 and 4 tumours a different gene, KDM6A, was inactivated by mutations. KDM6A works to remove methyl groups from H3K27, thus eliminating this gene’s function could keep cells in an immature dividing state. The results suggest the genes possibly work together to promote medulloblastoma development.
The EZH2 and KDM6A alterations were found only in the subgroup three and four tumours, which also had higher levels of H3K27 methylation than other medulloblastoma subtypes. ‘With this research we have ‘lifted the lid’ on the most aggressive and challenging form of medulloblastoma, subtype 3, which was really a black box in terms of our understanding, and revealed a major driver of the disease,’ Gilbertson said.
The findings add to mounting evidence from the Pediatric Cancer Genome Project that epigenetic changes play a pivotal role in fueling childhood cancer. Epigenetic mechanisms can serve as on-off switches, altering gene activity without changing the makeup of the gene. Such changes can lead to the unlimited cell growth of cancer.
St. Jude Children’s Research Hospital
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A new genetic mutation that causes familial amyotrophic lateral sclerosis (ALS), a fatal neurological disorder also known as Lou Gehrig’s Disease, has been identified by a team of scientists led by researchers at the University of Massachusetts Medical School (UMMS). Mutations to the profilin (PFN1) gene, which is essential to the growth and development of nerve cell axons, is estimated to account for one to two percent of inherited ALS cases. The finding points to defects in a neuron’s cytoskeleton structure as a potential common feature among diverse ALS genes.
‘This discovery identifies what may possibly be a common biological mechanism involved across familial ALS cases regardless of genetics,’ said John Landers, PhD, associate professor of neurology and senior author of the study. ‘We know of at least three other ALS genes, in addition to PFN1, that adversely impact axon growth. If indeed, this is part of the disease’s mechanism, then it might also be a potential target for therapeutics.’
Robert Brown, MD, DPhil, a co-author on the study and chair of neurology at UMass Medical School, said ‘Dr. Landers has done great work in defining this new pathway for motor neuron death. We are delighted to have identified the defects in families from the U.S., Israel and France that we have been investigating for several years. Our finding is particularly exciting because it may provide new insights into ALS treatment targets.’
ALS is a progressive, neurodegenerative disorder affecting the motor neurons in the central nervous system. As motor neurons die, the brain’s ability to send signals to the body’s muscles is compromised. This leads to loss of voluntary muscle movement, paralysis and eventually respiratory failure. The cause of most cases of ALS is not known. Approximately 10 percent of cases are inherited. Though investigators at UMass Medical School and elsewhere have identified several genes shown to cause inherited or familial ALS, almost 50 percent of these cases have an unknown genetic cause.
The current study details the discovery of the PFN1 gene mutation among two large ALS families. Both families were negative for known ALS-causing mutations and displayed familial relationships that suggested a dominant inheritance mode for the disease. For each family, two affected members with maximum genetic distance were selected for deep DNA sequencing. To identify an ALS-causing mutation, genetic variations between the family members were identified and screened against known databases of human genetic variation, such as the 1000 Genomes Project. This narrowed down the resulting number of candidate, ALS-causing mutations to two within the first family and three within the second. Interestingly, both families contained different mutations within the same gene – PFN1, the likely causative mutation. With additional screening, the team documented that in a total of 274 families sequenced, seven contained a mutation to the PFN1 gene, establishing it as a likely cause for ALS.
While it is not certain how the PFN1 mutation causes ALS, the cellular functions it controls within the motor neurons are responsible for regulation of a number of activities, including the growth and development of the axon, the slender projection through which neurons transmit electrical impulses to neighboring cells, such as muscle. When introduced into motor neuron cells, normal PFN1 protein was found diffused throughout the cytoplasm. Conversely, the mutant PFN1 observed in ALS patients was found to collect in dense aggregates, keeping it from functioning properly. Motor neurons producing mutated PFN1 showed markedly shorter axon outgrowth.
‘The discovery that mutant PFN1 interferes with axon outgrowth was very exciting to us,’ said Claudia Fallini, PhD, a postdoctoral researcher at Emory University School of Medicine who collaborated with the UMass Medical School authors to investigate PFN1’s functions in cultured motor neurons. ‘It suggests that alterations in actin dynamics may be an important mechanism at the basis of motor neuron degeneration.’
‘In healthy neurons, PFN1 acts almost like a railroad tie for fibrous filaments called actin, which make up the axon’ said Landers. ‘PFN1 helps bind these filaments to each other, promoting outgrowth of the axon. Without properly functioning PFN1 these filaments can’t come together. Here we show that mutant PFN1 may contribute to ALS pathogeneses by accumulating in these aggregates and altering the actin dynamics in a way that inhibits axon outgrowth.’
EurekAlert
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Many patients with acute myeloid leukemia (AML) share a mutation in a gene called IDH. A University of Colorado Cancer Center study shows that this IDH mutation may be the first domino in a chain that leads to a more aggressive form of the disease.
‘In fact, it’s not IDH itself that causes the problem,’ says Dan Pollyea, MD, MS, investigator at the CU Cancer Center and assistant professor of haematologic oncology at the University of Colorado School of Medicine. Rather, the mutation in IDH leads to exponentially higher blood levels of a protein called 2-hydroxyglutarate. This protein ‘mucks up,’ as Pollyea says, other genes that in turn promote cancer or fail to inhibit its growth.
The recent study shows that AML patients in remission who retain high levels of 2-hydroxyglutarate – due universally to IDH mutation – are much more likely to relapse than patients without similarly elevated levels.
The chain of causation includes another couple links.
‘2-hydroxyglutarate reduces genes’ ability to regulate themselves,’ says Pollyea. Over time genes accumulate gunk in the form of methylation – these methyl groups attach to silence parts of gene promoters, helping to decide which genes are and are not turned into proteins. Too much methylation is associated with many cancers, including AML. And 2-hydroxyglutarate turns off one of the body’s methylation-regulating genes.
So an IDH mutation leads to high 2-hydroxyglutarate, leads to bad gene regulation, leads to hypermethylation, leads to AML.
Pollyea hopes to stop the first domino from falling by targeting IDH mutations. ‘Imagine screening for patients prospectively and then if they have the mutation, we could use something like an IDH inhibitor,’ Pollyea says. Turn off this mutation and doctors may be able to turn of the disease, or at least its most aggressive characteristics.
But the genetic testing for IDH mutation is currently costly and time consuming. And so Pollyea hopes to identify patients with the IDH mutation by looking downstream – tests for blood-levels of 2-hydroxyglutarate being developed at the CU Cancer Center could determine the patients most likely to benefit from an IDH inhibitor.
Finally, Pollyea and colleagues including molecular biologist James DeGregori, PhD, are exploring novel ways to target the IDH mutation. ‘I think that even beyond the very real promise of IDH inhibitor drugs, this is a potential weak spot for AML that can be targeted in a number of ways,’ Pollyea says.
University of Colorado Cancer Center
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A book containing misprints may cause annoyance for the reader, but typos in an individual’s genetic blueprint (DNA) can mean serious disease or even death. The search for genetic correlates for the wide range of diseases plaguing humankind has inspired a wealth of research falling under the heading of genome-wide association studies (GWAS).
According to Sudhir Kumar, director of the Center for Evolutionary Medicine and Informatics at Arizona State University’s Biodesign Institute, however, results from many such studies become less useful when gene variants or alleles implicated in disease in a given population fail to be discovered in subsequent independent studies. ‘Often, we do not discover the same set of mutations for the same disease in different populations,’ he says. ‘This is a huge problem in genomic medicine.’
Kumar and colleagues Joel T. Dudley, Rong Chen, Maxwell Sanderford, and Atul J. Butte, have developed a statistical method to remedy this problem by using evolutionary information. It is capable of significantly enhancing the likelihood of identifying disease-associated alleles that show better consistency across populations, improving the reliability of GWAS studies. The method makes use of phylogenetics – the comparative study of species genomes through long-term evolutionary history.
The new method is now available to use via the web, so that researchers worldwide can apply it as an aid to discovering disease-associated mutations that are more consistently reproducible and therefore useable as diagnostic markers. Kumar refers to this new approach, combining standard comparative genomic studies with phylogenetic data as phylomedicine, a rapidly developing field that promises to streamline genomic information and improve its diagnostic power.
‘We can take this method and apply it to all the data that has been published,’ Kumar says. ‘It will lead to new discoveries that were sitting right there, but nobody knew about.’
The new method boosts the discovery of reproducible mutations by integrating evolutionary history of humans with contemporary genomic information. Applying the new rankings to a large GWAS study improved the discovery of reliable mutation correlates of complex diseases, which will advance personalised medicine based on each patient’s genomic code.
The basic idea behind GWAS is simple: compare the genomes of two populations of subjects, one with disease trait and a control group without the disease. Next, identify the disparities at each position of the genome in the two populations. Find the alleles occurring in the diseased population that are less frequent in the healthy population and you have just pinpointed the gene mutations associated with disease.
Or have you?
As Kumar explains, matters are not so simple. The mutations studied in such studies are known as SNPs (for single-nucleotide polymorphisms). This simply means that for a given gene sequence, one of the four nucleotides (A,T,C and G) found commonly in the population is replaced by something else. For example, the majority of healthy subjects may carry the ‘A’ at a particular position in the genome, but disease individuals may be more likely to carry a ‘C’ at the same position. If the difference between the groups is striking, the SNP may be associated with the disease trait.
Human genomes are vast structures – consisting of some 3 billion base pairs of nucleotides. Most are littered with SNPs and teasing out which ones sit there without apparent effect and which may translate to disease is often a vexing affair. For some diseases, a one-to-one correspondence between gene mutation and disease exists. Generally, these afflictions, known as monogenic diseases, have particular characteristics. They result from a mutation in just a single gene, rather than multiple genes. They are early-onset diseases, taking their toll when the patient is still young.
Monogenic diseases, which include cystic fibrosis, Tay sachs disease, sickle cell anemia and Huntington’s disease are usually not the targets for genome-wide association studies, because the relationship between gene mutation and occurrence of the disease is straightforward and reliable.
By contrast, so-called complex diseases tend to occur later in life, are triggered by mutations occurring at multiple sites along the genome and often have a significant environmental– that is, non-genetic – component. Finding the alleles responsible for such diseases, which include hypertension, rheumatoid arthritis, Alzheimer’s disease, type II diabetes and countless others through GWAS studies has often been a bewildering endeavor, as alleles identified in one study population frequently fail to turn up in different studies with different populations.
GWAS studies compute the odds of an allele along the genome being disease-related and translate this into a statistic known as the P value. Alleles with the lowest P value are least likely to have occurred by random chance. In the current research, a meta-analysis is conducted using results from thousands of previous GWAS studies and phylogenetics are applied to unearth evolutionary trends in the data.
‘Every position in the human genome among the billions of base pairs has evolved over time,’ Kumar says. ‘As the genome evolves, some positions permit change frequently while others do not.’ The positions least likely to change with time and across mammalian species are known as evolutionarily conserved positions. The group conducted a multispecies genomic analysis of 5,831 putative human risk variants for more than 230 disease phenotypes reported in 2,021 studies. ‘Even if a GWAS variant does not have a functional role in a disease, evolutionary information is still very relevant, because every position in the human genome has an evolutionary signature that gives us prior information on how alleles at that position are likely to vary in modern human populations,’ says Dudley, the study’s lead author.
An analysis of existing data found that most of the presumptively disease-related alleles uncovered in the GWAS studies occurred at relatively slow-evolving, highly conserved sites. According to Kumar, this fact accounts for the poor reproducibility of many putative disease alleles across different populations, as alleles occurring at conserved sites tend to be rare. As Kumar explains ‘You can keep finding rare alleles like this all day, but they would have limited clinical utility in a broader population.’
The new ranking system, known as E-ranking, incorporates phylogenetic information from multi-species studies of mammals, and applies it to human GWAS data. The effect is to remove the inherent sampling bias for rare alleles, allowing the more common alleles occurring at fast-evolving sites in the genome to be more readily discovered. ‘Our method removes this bias, which gives a boost to high-frequency common variants that are more likely to reproduce across populations due to the evolutionary history of the genomic position where they are found,’ says Dudley.
Arizona State University
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Cedars-Sinai researchers have linked Kawasaki Disease, a serious childhood illness that causes inflammation of blood vessels throughout the body, with early-onset and accelerated atherosclerosis, a leading cause of heart disease in adults.
In a study, an American Heart Association peer-reviewed medical journal, a team of researchers showed how Kawasaki Disease in young mice predisposed them to develop accelerated atherosclerosis, often called hardening of the arteries, in young adulthood. The study also suggests that aggressive early treatment of the blood vessel inflammation caused by Kawasaki Disease may reduce the future risk of developing accelerated atherosclerosis. Up to 25 percent of children with Kawasaki Disease will develop inflammation of the coronary arteries, making it the leading cause of acquired heart disease among children in developed countries.
‘Heart disease is the leading cause of death in this country and this study suggests that adult cardiovascular diseases likely start during childhood and that Kawasaki Disease may play a role in the childhood origin of adult heart disease,’ said Moshe Arditi, MD, executive vice chair of research in Cedars-Sinai’s Department of Pediatrics in the Maxine Dunitz Children’s Health Center and director of the Division of Pediatric Infectious Diseases and Immunology. ‘By recognising the connection between this vascular inflammatory disease and hardening of the arteries in young adults, physicians will be better prepared to provide preventive care to these vulnerable patients.’
Arditi said the study’s findings also may have implications for children with Kawasaki Disease in that they may need to be closely monitored for future development of early-onset atherosclerosis. Also, doctors treating children who have had Kawasaki Disease should closely monitor other known cardiovascular disease risk factors such as obesity, high blood pressure, high cholesterol and smoking, Arditi said.
Kawasaki Disease is diagnosed in approximately 5,000 U.S. children every year, predominantly affecting children younger than five. Boys are more likely than girls to acquire Kawasaki Disease, which starts with a sudden, persistent fever and causes swollen hands and feet, red eyes and body rash. Scientists suspect Kawasaki Disease is the body’s immune reaction to a virus that has yet to be identified.
Atherosclerosis occurs when fat, cholesterol, and other substances build up in the walls of arteries and form hard structures called plaques. Over the course of years, plaque buildup makes it harder for blood to flow because the plaque narrows arteries and makes them stiffer. When pieces of plaque break off and move to smaller vessels, they can cause stroke, heart attack or pulmonary embolism.
In the study, which was funded with a grant from the National Institute of Allergy and Infectious Diseases, mice with Kawasaki Disease were fed a high-fat diet and then compared to mice that did not have Kawasaki Disease but did eat the same high-fat diet. The Kawasaki mice developed significantly more atherosclerotic plaque at a younger age.
‘This study suggests that timely diagnosis and aggressive initial treatment of the vascular inflammation may be important in preventing this potentially serious future complication,’ said co-author Prediman K. Shah, MD, director of cardiology, director of the and the Shapell and Webb Family Chair in Clinical Cardiology at the Cedars-Sinai Heart Institute.
EurekAlert
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Scientists have discovered two genetic variants associated with the substantial, rapid weight gain occurring in nearly half the patients treated with antipsychotic medications, according to two studies involving the Centre for Addiction and Mental Health (CAMH).
These results could eventually be used to identify which patients have the variations, enabling clinicians to choose strategies to prevent this serious side-effect and offer more personalised treatment.
‘Weight gain occurs in up to 40 per cent of patients taking medications called second-generation or atypical antipsychotics, which are used because they’re effective in controlling the major symptoms of schizophrenia,’ says CAMH Scientist Dr. James Kennedy, senior author on the most recent study.
This weight gain can lead to obesity, type 2 diabetes, heart problems and a shortened life span. ‘Identifying genetic risks leading to these side-effects will help us prescribe more effectively,’ says Dr. Kennedy, head of the new Tanenbaum Centre for Pharmacogenetics, which is part of CAMH’s Campbell Family Mental Health Research Institute. Currently, CAMH screens for two other genetic variations that affect patients’ responses to psychiatric medications.
Each study identified a different variation near the melanocortin-4 receptor (MC4R) gene, which is known to be linked to obesity.
In the Archives of General Psychiatry study, people carrying two copies of a variant gained about three times as much weight as those with one or no copies, after six to 12 weeks of treatment with atypical antipsychotics. (The difference was approximately 6 kg versus 2 kg.) The study had four patient groups: two from the U.S., one in Germany and one from a larger European study.
‘The weight gain was associated with this genetic variation in all these groups, which included pediatric patients with severe behaviour or mood problems, and patients with schizophrenia experiencing a first episode or who did not respond to other antipsychotic treatments,’ says CAMH Scientist Dr. Daniel Müller. ‘The results from our genetic analysis combined with this diverse set of patients provide compelling evidence for the role of this MC4R variant. Our research group has discovered other gene variants associated with antipsychotic-induced weight gain in the past, but this one appears to be the most compelling finding thus far.’
Three of the four groups had never previously taken atypical antipsychotics. Different groups were treated with drugs such as olanzapine, risperidone, aripiprazole or quetiapine, and compliance was monitored to ensure the treatment regime was followed. Weight and other metabolic-related measures were taken at the start and during treatment.
A genome-wide association study was conducted on pediatric patients by the study’s lead researcher, Dr. Anil Malhotra, at the Zucker Hillside Hospital in Glen Oaks, NY. In this type of study, variations are sought across a person’s entire set of genes to identify those associated with a particular trait. The result pointed to the MC4R gene.
This gene’s role in antipsychotic-induced weight gain had been identified in a CAMH study published earlier this year in The Pharmacogenomics Journal, involving Drs. Müller and Kennedy, and conducted by PhD student Nabilah Chowdhury. They found a different variation on MC4R that was linked to the side-effect.
For both studies, CAMH researchers did genotyping experiments to identify the single changes to the sequence of the MC4R gene – known as single nucleotide polymorphisms (SNPs) – related to the drug-induced weight gain side-effect.
The MC4R gene encodes a receptor involved in the brain pathways regulating weight, appetite and satiety. ‘We don’t know exactly how the atypical antipsychotics disrupt this pathway, or how this variation affects the receptor,’ says Dr. Müller. ‘We need further studies to validate this result and eventually turn this into a clinical application.’
The Centre for Addiction and Mental Health
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Researchers at the Stanford University School of Medicine and Lucile Packard Children’s Hospital have identified several gene mutations responsible for the most common childhood brain tumour, called medulloblastoma, adding evidence to the theory that the diagnosis is a group of genetically distinct cancers with different prognoses. These and accompanying findings are likely to lead to less-toxic, better-targeted treatment approaches over the next two years, the researchers said.
‘We tend to treat all medulloblastomas as one disease without taking into account how heterogeneous the tumours are at the molecular level,’ said Yoon-Jae Cho, MD, an assistant professor of neurology and neurological sciences at Stanford, a pediatric neurologist at Packard Children’s and the senior author of the new research. ‘This paper represents a finer-grained view of the genetic landscape of these tumours and provides us with some leads on how to develop new therapies.’
The research is part of a large, ongoing effort to characterise genetic errors in medulloblastoma. Two companion studies on which Cho is a co-author will be published simultaneously with his paper. The three papers came from a consortium that involves scientists at Stanford, Packard Children’s, the Broad Institute, Children’s Hospital Boston, the Dana-Farber Cancer Institute, the German Cancer Research Center, Brandeis University and the Hospital for Sick Children in Toronto.
Current treatment for medulloblastoma, which originates in the cerebellum and affects about 250 U.S. children each year, begins with surgery to remove as much of the tumour as possible. Patients then receive a combination of radiation and chemotherapy, but the treatments are not tailored to the tumour’s genetic characteristics.
Cho’s team extracted DNA from 92 medulloblastoma tumours and compared it with DNA from matched blood samples from the same patients, uncovering 12 significant ‘point mutations’ — single-letter errors in the genetic code — that occurred frequently in the brain cancer. A handful of the mutations had been previously identified in smaller studies of medulloblastoma, but several mutations were novel in both medulloblastoma and in cancer.
Among the newly identified mutations was one in an RNA helicase gene, DDX3X, which Cho said is the second-most common mutation in medulloblastoma tumours. ‘Mutations in this gene have now also been identified in other tumour types, such as chronic lymphocytic leukaemia, and head and neck tumours,’ he said.
However, the researchers found that it was rare for the same gene mutated in several different patients’ tumours. More commonly, mutations involving a set of genes regulating a single biological pathway were found in the tumours — a pattern that is emerging across cancer genome sequencing efforts.
Though no single tumour in the study carried all 12 mutations, the researchers were able to categorise the tumours according to which mutations they possessed. ‘We now understand that there are certain tumours with particular genetic signatures that are really resistant to standard treatments,’ Cho said. Children with medulloblastoma do not routinely have their tumours’ genetic signatures characterised, but Cho believes that such characterisation coupled with targeted therapies could greatly enhance tumour treatment.
About two-thirds of medulloblastoma patients now survive five years past diagnosis, but many survivors suffer lasting physical or intellectual side effects from their cancer treatments. Drugs tailored to a tumour’s genetic profile have the potential to save more patients while reducing side effects, Cho said.
Several of the mutations discovered affect cellular signals that switch large groups of genes on and off. ‘The dysregulation of these ‘epigenetic programs’ is becoming a common theme not only in medulloblastoma but across cancer,’ Cho said. Such pathways may be good targets for cancer drugs; indeed, drugs targeting one such pathway (histone methyltransferases) are currently in pre-clinical development, while agents against another pathway (Hedgehog signaling pathway) are entering phase-2 clinical trials for medulloblastoma.
EurekAlert
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A research study led by the Peninsula College of Medicine and Dentistry, University of Exeter, and Boston University School of Medicine, in collaboration with a global consortium, has identified genetic markers that influence a protein involved in regulating oestrogen and testosterone levels in the bloodstream.
The results also reveal that some of the genetic markers for this protein are near genes related to liver function, metabolism and type 2 diabetes, demonstrating an important genetic connection between the metabolic and reproductive systems in men and women.
The study was carried out in collaboration with the Framingham Heart Study and investigators from 15 international epidemiologic studies participating in the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium.
Sex hormone binding globulin (SHBG) is the key protein that carries testosterone and oestrogen in the bloodstream in both men and women. As the main carrier of these sex hormones, SHBG helps to regulate their effects in different tissues and organs in the body. In addition to effects on reproduction in men and women through regulation of sex hormones, SHBG has been linked to many chronic diseases including type 2 diabetes and hormone-sensitive cancers such as breast and prostate.
Previous family studies have demonstrated that approximately 50 per cent of the variation in SHBG concentrations in the bloodstream is inherited from parents, suggesting that SHBG levels are under significant genetic control. However, little has been known about the specific genes that influence SHBG levels.
Investigators examined human genomes from 21,791 men and women to determine which genes influence SHBG levels and validated the results from this genome-wide association study (GWAS) in an additional 7,046 men and women. They identified 12 single-nucleotide polymorphisms (SNPs), or DNA sequence variations, associated with the concentration of SHBG circulating in the bloodstream. Although these genetic variants only explain a small fraction of the sex hormone variability seen between individuals, they could provide insight into the diseases connected to sex hormone regulation.
The results showed that the SNPs that influence SHBG levels are near genes related to liver function, fat and carbohydrate metabolism and type 2 diabetes. In addition, there were genes that had stronger effects in one sex compared to the other.
‘These findings highlight the diverse range of biological processes that may be impacted by sex hormone regulation,’ said Dr. John Perry of the Peninsula College of Medicine and Dentistry, University of Exeter.
EurekAlert
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Scientists behind Olympic Team GB are working on genetic tests to understand why some athletes are prone to injury, BBC’s Newsnight has learned.
Tendon injuries and stress fractures are common in elite athletes, but how and why they happen is less clear.
University College London’s Prof Hugh Montgomery says they have found a gene they think strongly influences the risk of stress fracture and more will come.
It is hoped the research will allow training to be individually tailored.
Diet, repetitive strain and loading are all known to play a part, and scientists say there is clearly a strong genetic element.
Director of the Institute for Human Health and Performance at University College London, Prof Montgomery carried out groundbreaking work on genes and fitness in the 1990s, most notably the ‘ACE’ gene, thought to be linked to endurance.
‘If we understood that genetic component we would have a much better understanding of the patho-physiology – the disease processes that let that happen,’ says Prof Montgomery.
He has been working closely with the English Institute of Sport (EIS), which aims to apply the latest in sports science and medicine for the benefit of Britain’s Olympic and Paralympic athletes.
EIS’s Director of Sport Science, Dr Ken van Someren, told Newsnight he is keen to apply the latest genetics discoveries.
‘If we can identify some particular genes that are associated with a higher risk of injury in certain individuals, and we think we’re close, we can tailor the training, conditioning and preparation that we put those individuals through.’
He added that should injury occur, the research could also influence the medical treatment the person receives.
But Dr van Someren stressed that there is no intention to use genes as a means of identifying sporting talent.
He says that for many people sport is about a fun and healthy lifestyle and genetics should not be used to screen people in or out of sport, adding that although genes might tell us a lot about the likelihood or probability of success, it is not an absolute science and there would be a danger of ‘missing out on some future champions.’
Prof Montgomery believes that looking for tomorrow’s sporting champions should involve looking at a combination of genes and the environment, rather than just relying on screening the genome.
He says we should look a person’s performance and dedication and to the sport rather than trying to ‘predict that dedication and performance by gene screening.’
BBC
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The pluripotency factor LIN28 in monkey and human testis: a marker for spermatogonial stem cells?
, /in E-News /by 3wmediaMammalian spermatogenesis is maintained by spermatogonial stem cells (SSCs). However, since evidentiary assays and unequivocal markers are still missing in non-human primates and man, the identity of primate SSCs is unknown. In contrast, in the mouse, germ cell transplantation studies functionally demonstrated the presence of SSCs. LIN28 is an RNA-binding pluripotent stem cell factor, which is also strongly expressed in undifferentiated mouse spermatogonia. By contrast, two recent reports indicated that LIN28 is completely absent from adult human testes. Here, we analysed LIN28 expression in marmoset monkey (Callithrix jacchus) and human testes during development and adulthood and compared it with the mouse. In the marmoset, LIN28 was strongly expressed in migratory PGCs and gonocytes. Strikingly, we found a rare LIN28-positive subpopulation of spermatogonia also in the adult marmoset testis. This was corroborated by western blotting and quantitative RT-PCR. Importantly, in contrast to previous publications, we found LIN28-positive spermatogonia also in normal adult human and additional adult non-human primate testes. Some seasonal breeders exhibit a degenerated (involuted) germinal epithelium during their non-breeding season consisting only of Sertoli cells and SSCs. The latter re-initiate spermatogenesis prior to the next breeding-season. Fully involuted testes from a seasonal hamster and NHP (Lemur catta) exhibited numerous LIN28-positive spermatogonia, indicating a SSC-identity of the labeled cells. We conclude that LIN28 is differentially expressed in mouse and non-human primate spermatogonia and might be a marker for a rare SSC population in non-human primates and man. Further characterization of the LIN28-positive population is required. European Society of Human Reproduction and Embryology
Gene sequencing project identifies potential drug targets in common childhood brain tumour
, /in E-News /by 3wmediaResearchers studying the genetic roots of the most common malignant childhood brain tumour have discovered missteps in three of the four subtypes of the cancer that involve genes already targeted for drug development.
The most significant gene alterations are linked to subtypes of medulloblastoma that currently have the best and worst prognosis. They were among 41 genes associated for the first time to medulloblastoma by the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project.
‘This study provides new direction for understanding what drives these tumours and uncovers totally unexpected new drug targets. There are drugs already in development against these targets aimed at treating adult cancers and other diseases,’ said Richard Gilbertson, M.D., Ph.D., St. Jude Comprehensive Cancer Center director. Gilbertson and Jinghui Zhang, Ph.D., an associate member of the St. Jude Department of Computational Biology, are the study’s corresponding authors.
The results mark progress toward more targeted therapies against medulloblastoma and other cancers. While better use of existing drugs and improved supportive care have helped push long-term survival rates for childhood cancer to about 80 percent, drug development efforts have largely stalled for more than two decades, particularly against pediatric brain tumours.
‘This study is a great example of the way whole-genome sequencing of cancer patients allows us to dig deep into the biology of certain tumors and catch a glimpse of their Achilles heel,’ said co-author Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis. ‘These results help us better understand the disease and, as a result, we will be able to more effectively diagnose and treat these kids.’
This study involved sequencing the complete normal and cancer genomes of 37 young patients with medulloblastoma, making it the largest such effort to date involving the cancer. Researchers then checked tumours from an additional 56 patients for the same alterations.
The findings are part of the Pediatric Cancer Genome Project, which launched in 2010 as a three-year effort to decipher the complete normal and tumour genomes of 600 young cancer patients with some of the most challenging tumours. The endeavour has already yielded important clues into the origin, spread and treatment response in childhood cancers of the blood, brain, eye and nervous system.
Medulloblastoma is diagnosed in about 400 U.S. children and adolescents annually. Their outcome varies widely based on the subtype they have. While nearly all patients with the wingless (WNT) subtype survive, just 60 percent of those with subtype 3 medulloblastoma are alive three years after diagnosis. WNT medulloblastoma is named for the pathway disrupted in the tumor subtype.
This study found a high percentage of patients with WNT-subtype medulloblastoma had mutations in the DDX3X gene. The investigators found evidence that mutated DDX3X is required to sustain the brain cells where WNT subtype tumours develop. The research also found evidence linking alterations in other genes, including CDH1 and PIK3CA, to the development and spread of the WNT subtype. ‘It is particularly exciting that these genes, or the pathways in which they work, are already the focus of drug development efforts. This opens up the possibility of using these drugs to treat medulloblastoma in new ways,’ said Giles Robinson, M.D., St. Jude Department of Oncology research associate and one of the study’s first authors.
Investigators demonstrated that subtype three and four medulloblastoma often had alterations in genes that impact cell maturation. The genes carry instructions for proteins that add or remove the chemical group methyl to the H3K27 protein. H3K27 is part of the chromatin structure that packages DNA to fit inside cells. That packaging helps determine if genes are switched on or off. The addition of methyl to H3K27 permits less specialised cells to keep dividing and blocks activity of genes that would prompt cells to stop dividing, differentiate and take on more specialised roles.
Some subgroup 3 and 4 tumours were characterised by a gain in EZH2, which adds methyl to H3K27. EZH2 is also associated with adult cancers and the focus of ongoing drug development. St. Jude has begun screening those and other compounds for evidence of effectiveness against medulloblastoma.
In other subtype 3 and 4 tumours a different gene, KDM6A, was inactivated by mutations. KDM6A works to remove methyl groups from H3K27, thus eliminating this gene’s function could keep cells in an immature dividing state. The results suggest the genes possibly work together to promote medulloblastoma development.
The EZH2 and KDM6A alterations were found only in the subgroup three and four tumours, which also had higher levels of H3K27 methylation than other medulloblastoma subtypes. ‘With this research we have ‘lifted the lid’ on the most aggressive and challenging form of medulloblastoma, subtype 3, which was really a black box in terms of our understanding, and revealed a major driver of the disease,’ Gilbertson said.
The findings add to mounting evidence from the Pediatric Cancer Genome Project that epigenetic changes play a pivotal role in fueling childhood cancer. Epigenetic mechanisms can serve as on-off switches, altering gene activity without changing the makeup of the gene. Such changes can lead to the unlimited cell growth of cancer. St. Jude Children’s Research Hospital
Researchers isolate gene mutations in patients with inherited amyotrophic lateral sclerosis
, /in E-News /by 3wmediaA new genetic mutation that causes familial amyotrophic lateral sclerosis (ALS), a fatal neurological disorder also known as Lou Gehrig’s Disease, has been identified by a team of scientists led by researchers at the University of Massachusetts Medical School (UMMS). Mutations to the profilin (PFN1) gene, which is essential to the growth and development of nerve cell axons, is estimated to account for one to two percent of inherited ALS cases. The finding points to defects in a neuron’s cytoskeleton structure as a potential common feature among diverse ALS genes.
‘This discovery identifies what may possibly be a common biological mechanism involved across familial ALS cases regardless of genetics,’ said John Landers, PhD, associate professor of neurology and senior author of the study. ‘We know of at least three other ALS genes, in addition to PFN1, that adversely impact axon growth. If indeed, this is part of the disease’s mechanism, then it might also be a potential target for therapeutics.’
Robert Brown, MD, DPhil, a co-author on the study and chair of neurology at UMass Medical School, said ‘Dr. Landers has done great work in defining this new pathway for motor neuron death. We are delighted to have identified the defects in families from the U.S., Israel and France that we have been investigating for several years. Our finding is particularly exciting because it may provide new insights into ALS treatment targets.’
ALS is a progressive, neurodegenerative disorder affecting the motor neurons in the central nervous system. As motor neurons die, the brain’s ability to send signals to the body’s muscles is compromised. This leads to loss of voluntary muscle movement, paralysis and eventually respiratory failure. The cause of most cases of ALS is not known. Approximately 10 percent of cases are inherited. Though investigators at UMass Medical School and elsewhere have identified several genes shown to cause inherited or familial ALS, almost 50 percent of these cases have an unknown genetic cause.
The current study details the discovery of the PFN1 gene mutation among two large ALS families. Both families were negative for known ALS-causing mutations and displayed familial relationships that suggested a dominant inheritance mode for the disease. For each family, two affected members with maximum genetic distance were selected for deep DNA sequencing. To identify an ALS-causing mutation, genetic variations between the family members were identified and screened against known databases of human genetic variation, such as the 1000 Genomes Project. This narrowed down the resulting number of candidate, ALS-causing mutations to two within the first family and three within the second. Interestingly, both families contained different mutations within the same gene – PFN1, the likely causative mutation. With additional screening, the team documented that in a total of 274 families sequenced, seven contained a mutation to the PFN1 gene, establishing it as a likely cause for ALS.
While it is not certain how the PFN1 mutation causes ALS, the cellular functions it controls within the motor neurons are responsible for regulation of a number of activities, including the growth and development of the axon, the slender projection through which neurons transmit electrical impulses to neighboring cells, such as muscle. When introduced into motor neuron cells, normal PFN1 protein was found diffused throughout the cytoplasm. Conversely, the mutant PFN1 observed in ALS patients was found to collect in dense aggregates, keeping it from functioning properly. Motor neurons producing mutated PFN1 showed markedly shorter axon outgrowth.
‘The discovery that mutant PFN1 interferes with axon outgrowth was very exciting to us,’ said Claudia Fallini, PhD, a postdoctoral researcher at Emory University School of Medicine who collaborated with the UMass Medical School authors to investigate PFN1’s functions in cultured motor neurons. ‘It suggests that alterations in actin dynamics may be an important mechanism at the basis of motor neuron degeneration.’
‘In healthy neurons, PFN1 acts almost like a railroad tie for fibrous filaments called actin, which make up the axon’ said Landers. ‘PFN1 helps bind these filaments to each other, promoting outgrowth of the axon. Without properly functioning PFN1 these filaments can’t come together. Here we show that mutant PFN1 may contribute to ALS pathogeneses by accumulating in these aggregates and altering the actin dynamics in a way that inhibits axon outgrowth.’ EurekAlert
Mutation in gene IDH a possible target for AML treatment
, /in E-News /by 3wmediaMany patients with acute myeloid leukemia (AML) share a mutation in a gene called IDH. A University of Colorado Cancer Center study shows that this IDH mutation may be the first domino in a chain that leads to a more aggressive form of the disease.
‘In fact, it’s not IDH itself that causes the problem,’ says Dan Pollyea, MD, MS, investigator at the CU Cancer Center and assistant professor of haematologic oncology at the University of Colorado School of Medicine. Rather, the mutation in IDH leads to exponentially higher blood levels of a protein called 2-hydroxyglutarate. This protein ‘mucks up,’ as Pollyea says, other genes that in turn promote cancer or fail to inhibit its growth.
The recent study shows that AML patients in remission who retain high levels of 2-hydroxyglutarate – due universally to IDH mutation – are much more likely to relapse than patients without similarly elevated levels.
The chain of causation includes another couple links.
‘2-hydroxyglutarate reduces genes’ ability to regulate themselves,’ says Pollyea. Over time genes accumulate gunk in the form of methylation – these methyl groups attach to silence parts of gene promoters, helping to decide which genes are and are not turned into proteins. Too much methylation is associated with many cancers, including AML. And 2-hydroxyglutarate turns off one of the body’s methylation-regulating genes.
So an IDH mutation leads to high 2-hydroxyglutarate, leads to bad gene regulation, leads to hypermethylation, leads to AML.
Pollyea hopes to stop the first domino from falling by targeting IDH mutations. ‘Imagine screening for patients prospectively and then if they have the mutation, we could use something like an IDH inhibitor,’ Pollyea says. Turn off this mutation and doctors may be able to turn of the disease, or at least its most aggressive characteristics.
But the genetic testing for IDH mutation is currently costly and time consuming. And so Pollyea hopes to identify patients with the IDH mutation by looking downstream – tests for blood-levels of 2-hydroxyglutarate being developed at the CU Cancer Center could determine the patients most likely to benefit from an IDH inhibitor.
Finally, Pollyea and colleagues including molecular biologist James DeGregori, PhD, are exploring novel ways to target the IDH mutation. ‘I think that even beyond the very real promise of IDH inhibitor drugs, this is a potential weak spot for AML that can be targeted in a number of ways,’ Pollyea says. University of Colorado Cancer Center
Evolutionary information improves discovery of mutations associated with diseases
, /in E-News /by 3wmediaA book containing misprints may cause annoyance for the reader, but typos in an individual’s genetic blueprint (DNA) can mean serious disease or even death. The search for genetic correlates for the wide range of diseases plaguing humankind has inspired a wealth of research falling under the heading of genome-wide association studies (GWAS).
According to Sudhir Kumar, director of the Center for Evolutionary Medicine and Informatics at Arizona State University’s Biodesign Institute, however, results from many such studies become less useful when gene variants or alleles implicated in disease in a given population fail to be discovered in subsequent independent studies. ‘Often, we do not discover the same set of mutations for the same disease in different populations,’ he says. ‘This is a huge problem in genomic medicine.’
Kumar and colleagues Joel T. Dudley, Rong Chen, Maxwell Sanderford, and Atul J. Butte, have developed a statistical method to remedy this problem by using evolutionary information. It is capable of significantly enhancing the likelihood of identifying disease-associated alleles that show better consistency across populations, improving the reliability of GWAS studies. The method makes use of phylogenetics – the comparative study of species genomes through long-term evolutionary history.
The new method is now available to use via the web, so that researchers worldwide can apply it as an aid to discovering disease-associated mutations that are more consistently reproducible and therefore useable as diagnostic markers. Kumar refers to this new approach, combining standard comparative genomic studies with phylogenetic data as phylomedicine, a rapidly developing field that promises to streamline genomic information and improve its diagnostic power.
‘We can take this method and apply it to all the data that has been published,’ Kumar says. ‘It will lead to new discoveries that were sitting right there, but nobody knew about.’
The new method boosts the discovery of reproducible mutations by integrating evolutionary history of humans with contemporary genomic information. Applying the new rankings to a large GWAS study improved the discovery of reliable mutation correlates of complex diseases, which will advance personalised medicine based on each patient’s genomic code.
The basic idea behind GWAS is simple: compare the genomes of two populations of subjects, one with disease trait and a control group without the disease. Next, identify the disparities at each position of the genome in the two populations. Find the alleles occurring in the diseased population that are less frequent in the healthy population and you have just pinpointed the gene mutations associated with disease.
Or have you?
As Kumar explains, matters are not so simple. The mutations studied in such studies are known as SNPs (for single-nucleotide polymorphisms). This simply means that for a given gene sequence, one of the four nucleotides (A,T,C and G) found commonly in the population is replaced by something else. For example, the majority of healthy subjects may carry the ‘A’ at a particular position in the genome, but disease individuals may be more likely to carry a ‘C’ at the same position. If the difference between the groups is striking, the SNP may be associated with the disease trait.
Human genomes are vast structures – consisting of some 3 billion base pairs of nucleotides. Most are littered with SNPs and teasing out which ones sit there without apparent effect and which may translate to disease is often a vexing affair. For some diseases, a one-to-one correspondence between gene mutation and disease exists. Generally, these afflictions, known as monogenic diseases, have particular characteristics. They result from a mutation in just a single gene, rather than multiple genes. They are early-onset diseases, taking their toll when the patient is still young.
Monogenic diseases, which include cystic fibrosis, Tay sachs disease, sickle cell anemia and Huntington’s disease are usually not the targets for genome-wide association studies, because the relationship between gene mutation and occurrence of the disease is straightforward and reliable.
By contrast, so-called complex diseases tend to occur later in life, are triggered by mutations occurring at multiple sites along the genome and often have a significant environmental– that is, non-genetic – component. Finding the alleles responsible for such diseases, which include hypertension, rheumatoid arthritis, Alzheimer’s disease, type II diabetes and countless others through GWAS studies has often been a bewildering endeavor, as alleles identified in one study population frequently fail to turn up in different studies with different populations.
GWAS studies compute the odds of an allele along the genome being disease-related and translate this into a statistic known as the P value. Alleles with the lowest P value are least likely to have occurred by random chance. In the current research, a meta-analysis is conducted using results from thousands of previous GWAS studies and phylogenetics are applied to unearth evolutionary trends in the data.
‘Every position in the human genome among the billions of base pairs has evolved over time,’ Kumar says. ‘As the genome evolves, some positions permit change frequently while others do not.’ The positions least likely to change with time and across mammalian species are known as evolutionarily conserved positions. The group conducted a multispecies genomic analysis of 5,831 putative human risk variants for more than 230 disease phenotypes reported in 2,021 studies. ‘Even if a GWAS variant does not have a functional role in a disease, evolutionary information is still very relevant, because every position in the human genome has an evolutionary signature that gives us prior information on how alleles at that position are likely to vary in modern human populations,’ says Dudley, the study’s lead author.
An analysis of existing data found that most of the presumptively disease-related alleles uncovered in the GWAS studies occurred at relatively slow-evolving, highly conserved sites. According to Kumar, this fact accounts for the poor reproducibility of many putative disease alleles across different populations, as alleles occurring at conserved sites tend to be rare. As Kumar explains ‘You can keep finding rare alleles like this all day, but they would have limited clinical utility in a broader population.’
The new ranking system, known as E-ranking, incorporates phylogenetic information from multi-species studies of mammals, and applies it to human GWAS data. The effect is to remove the inherent sampling bias for rare alleles, allowing the more common alleles occurring at fast-evolving sites in the genome to be more readily discovered. ‘Our method removes this bias, which gives a boost to high-frequency common variants that are more likely to reproduce across populations due to the evolutionary history of the genomic position where they are found,’ says Dudley. Arizona State University
Researchers link Kawasaki Disease in childhood with increased risk of adult heart disease
, /in E-News /by 3wmediaCedars-Sinai researchers have linked Kawasaki Disease, a serious childhood illness that causes inflammation of blood vessels throughout the body, with early-onset and accelerated atherosclerosis, a leading cause of heart disease in adults.
In a study, an American Heart Association peer-reviewed medical journal, a team of researchers showed how Kawasaki Disease in young mice predisposed them to develop accelerated atherosclerosis, often called hardening of the arteries, in young adulthood. The study also suggests that aggressive early treatment of the blood vessel inflammation caused by Kawasaki Disease may reduce the future risk of developing accelerated atherosclerosis. Up to 25 percent of children with Kawasaki Disease will develop inflammation of the coronary arteries, making it the leading cause of acquired heart disease among children in developed countries.
‘Heart disease is the leading cause of death in this country and this study suggests that adult cardiovascular diseases likely start during childhood and that Kawasaki Disease may play a role in the childhood origin of adult heart disease,’ said Moshe Arditi, MD, executive vice chair of research in Cedars-Sinai’s Department of Pediatrics in the Maxine Dunitz Children’s Health Center and director of the Division of Pediatric Infectious Diseases and Immunology. ‘By recognising the connection between this vascular inflammatory disease and hardening of the arteries in young adults, physicians will be better prepared to provide preventive care to these vulnerable patients.’
Arditi said the study’s findings also may have implications for children with Kawasaki Disease in that they may need to be closely monitored for future development of early-onset atherosclerosis. Also, doctors treating children who have had Kawasaki Disease should closely monitor other known cardiovascular disease risk factors such as obesity, high blood pressure, high cholesterol and smoking, Arditi said.
Kawasaki Disease is diagnosed in approximately 5,000 U.S. children every year, predominantly affecting children younger than five. Boys are more likely than girls to acquire Kawasaki Disease, which starts with a sudden, persistent fever and causes swollen hands and feet, red eyes and body rash. Scientists suspect Kawasaki Disease is the body’s immune reaction to a virus that has yet to be identified.
Atherosclerosis occurs when fat, cholesterol, and other substances build up in the walls of arteries and form hard structures called plaques. Over the course of years, plaque buildup makes it harder for blood to flow because the plaque narrows arteries and makes them stiffer. When pieces of plaque break off and move to smaller vessels, they can cause stroke, heart attack or pulmonary embolism.
In the study, which was funded with a grant from the National Institute of Allergy and Infectious Diseases, mice with Kawasaki Disease were fed a high-fat diet and then compared to mice that did not have Kawasaki Disease but did eat the same high-fat diet. The Kawasaki mice developed significantly more atherosclerotic plaque at a younger age.
‘This study suggests that timely diagnosis and aggressive initial treatment of the vascular inflammation may be important in preventing this potentially serious future complication,’ said co-author Prediman K. Shah, MD, director of cardiology, director of the and the Shapell and Webb Family Chair in Clinical Cardiology at the Cedars-Sinai Heart Institute. EurekAlert
Genetic link to rapid weight gain from antipsychotics discovered
, /in E-News /by 3wmediaScientists have discovered two genetic variants associated with the substantial, rapid weight gain occurring in nearly half the patients treated with antipsychotic medications, according to two studies involving the Centre for Addiction and Mental Health (CAMH).
These results could eventually be used to identify which patients have the variations, enabling clinicians to choose strategies to prevent this serious side-effect and offer more personalised treatment.
‘Weight gain occurs in up to 40 per cent of patients taking medications called second-generation or atypical antipsychotics, which are used because they’re effective in controlling the major symptoms of schizophrenia,’ says CAMH Scientist Dr. James Kennedy, senior author on the most recent study.
This weight gain can lead to obesity, type 2 diabetes, heart problems and a shortened life span. ‘Identifying genetic risks leading to these side-effects will help us prescribe more effectively,’ says Dr. Kennedy, head of the new Tanenbaum Centre for Pharmacogenetics, which is part of CAMH’s Campbell Family Mental Health Research Institute. Currently, CAMH screens for two other genetic variations that affect patients’ responses to psychiatric medications.
Each study identified a different variation near the melanocortin-4 receptor (MC4R) gene, which is known to be linked to obesity.
In the Archives of General Psychiatry study, people carrying two copies of a variant gained about three times as much weight as those with one or no copies, after six to 12 weeks of treatment with atypical antipsychotics. (The difference was approximately 6 kg versus 2 kg.) The study had four patient groups: two from the U.S., one in Germany and one from a larger European study.
‘The weight gain was associated with this genetic variation in all these groups, which included pediatric patients with severe behaviour or mood problems, and patients with schizophrenia experiencing a first episode or who did not respond to other antipsychotic treatments,’ says CAMH Scientist Dr. Daniel Müller. ‘The results from our genetic analysis combined with this diverse set of patients provide compelling evidence for the role of this MC4R variant. Our research group has discovered other gene variants associated with antipsychotic-induced weight gain in the past, but this one appears to be the most compelling finding thus far.’
Three of the four groups had never previously taken atypical antipsychotics. Different groups were treated with drugs such as olanzapine, risperidone, aripiprazole or quetiapine, and compliance was monitored to ensure the treatment regime was followed. Weight and other metabolic-related measures were taken at the start and during treatment.
A genome-wide association study was conducted on pediatric patients by the study’s lead researcher, Dr. Anil Malhotra, at the Zucker Hillside Hospital in Glen Oaks, NY. In this type of study, variations are sought across a person’s entire set of genes to identify those associated with a particular trait. The result pointed to the MC4R gene.
This gene’s role in antipsychotic-induced weight gain had been identified in a CAMH study published earlier this year in The Pharmacogenomics Journal, involving Drs. Müller and Kennedy, and conducted by PhD student Nabilah Chowdhury. They found a different variation on MC4R that was linked to the side-effect.
For both studies, CAMH researchers did genotyping experiments to identify the single changes to the sequence of the MC4R gene – known as single nucleotide polymorphisms (SNPs) – related to the drug-induced weight gain side-effect.
The MC4R gene encodes a receptor involved in the brain pathways regulating weight, appetite and satiety. ‘We don’t know exactly how the atypical antipsychotics disrupt this pathway, or how this variation affects the receptor,’ says Dr. Müller. ‘We need further studies to validate this result and eventually turn this into a clinical application.’ The Centre for Addiction and Mental Health
Genetic mutations that cause common childhood brain tumours identified
, /in E-News /by 3wmediaResearchers at the Stanford University School of Medicine and Lucile Packard Children’s Hospital have identified several gene mutations responsible for the most common childhood brain tumour, called medulloblastoma, adding evidence to the theory that the diagnosis is a group of genetically distinct cancers with different prognoses. These and accompanying findings are likely to lead to less-toxic, better-targeted treatment approaches over the next two years, the researchers said.
‘We tend to treat all medulloblastomas as one disease without taking into account how heterogeneous the tumours are at the molecular level,’ said Yoon-Jae Cho, MD, an assistant professor of neurology and neurological sciences at Stanford, a pediatric neurologist at Packard Children’s and the senior author of the new research. ‘This paper represents a finer-grained view of the genetic landscape of these tumours and provides us with some leads on how to develop new therapies.’
The research is part of a large, ongoing effort to characterise genetic errors in medulloblastoma. Two companion studies on which Cho is a co-author will be published simultaneously with his paper. The three papers came from a consortium that involves scientists at Stanford, Packard Children’s, the Broad Institute, Children’s Hospital Boston, the Dana-Farber Cancer Institute, the German Cancer Research Center, Brandeis University and the Hospital for Sick Children in Toronto.
Current treatment for medulloblastoma, which originates in the cerebellum and affects about 250 U.S. children each year, begins with surgery to remove as much of the tumour as possible. Patients then receive a combination of radiation and chemotherapy, but the treatments are not tailored to the tumour’s genetic characteristics.
Cho’s team extracted DNA from 92 medulloblastoma tumours and compared it with DNA from matched blood samples from the same patients, uncovering 12 significant ‘point mutations’ — single-letter errors in the genetic code — that occurred frequently in the brain cancer. A handful of the mutations had been previously identified in smaller studies of medulloblastoma, but several mutations were novel in both medulloblastoma and in cancer.
Among the newly identified mutations was one in an RNA helicase gene, DDX3X, which Cho said is the second-most common mutation in medulloblastoma tumours. ‘Mutations in this gene have now also been identified in other tumour types, such as chronic lymphocytic leukaemia, and head and neck tumours,’ he said.
However, the researchers found that it was rare for the same gene mutated in several different patients’ tumours. More commonly, mutations involving a set of genes regulating a single biological pathway were found in the tumours — a pattern that is emerging across cancer genome sequencing efforts.
Though no single tumour in the study carried all 12 mutations, the researchers were able to categorise the tumours according to which mutations they possessed. ‘We now understand that there are certain tumours with particular genetic signatures that are really resistant to standard treatments,’ Cho said. Children with medulloblastoma do not routinely have their tumours’ genetic signatures characterised, but Cho believes that such characterisation coupled with targeted therapies could greatly enhance tumour treatment.
About two-thirds of medulloblastoma patients now survive five years past diagnosis, but many survivors suffer lasting physical or intellectual side effects from their cancer treatments. Drugs tailored to a tumour’s genetic profile have the potential to save more patients while reducing side effects, Cho said.
Several of the mutations discovered affect cellular signals that switch large groups of genes on and off. ‘The dysregulation of these ‘epigenetic programs’ is becoming a common theme not only in medulloblastoma but across cancer,’ Cho said. Such pathways may be good targets for cancer drugs; indeed, drugs targeting one such pathway (histone methyltransferases) are currently in pre-clinical development, while agents against another pathway (Hedgehog signaling pathway) are entering phase-2 clinical trials for medulloblastoma. EurekAlert
Genetic markers for testosterone and oestrogen level regulation identified
, /in E-News /by 3wmediaA research study led by the Peninsula College of Medicine and Dentistry, University of Exeter, and Boston University School of Medicine, in collaboration with a global consortium, has identified genetic markers that influence a protein involved in regulating oestrogen and testosterone levels in the bloodstream.
The results also reveal that some of the genetic markers for this protein are near genes related to liver function, metabolism and type 2 diabetes, demonstrating an important genetic connection between the metabolic and reproductive systems in men and women.
The study was carried out in collaboration with the Framingham Heart Study and investigators from 15 international epidemiologic studies participating in the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium.
Sex hormone binding globulin (SHBG) is the key protein that carries testosterone and oestrogen in the bloodstream in both men and women. As the main carrier of these sex hormones, SHBG helps to regulate their effects in different tissues and organs in the body. In addition to effects on reproduction in men and women through regulation of sex hormones, SHBG has been linked to many chronic diseases including type 2 diabetes and hormone-sensitive cancers such as breast and prostate.
Previous family studies have demonstrated that approximately 50 per cent of the variation in SHBG concentrations in the bloodstream is inherited from parents, suggesting that SHBG levels are under significant genetic control. However, little has been known about the specific genes that influence SHBG levels.
Investigators examined human genomes from 21,791 men and women to determine which genes influence SHBG levels and validated the results from this genome-wide association study (GWAS) in an additional 7,046 men and women. They identified 12 single-nucleotide polymorphisms (SNPs), or DNA sequence variations, associated with the concentration of SHBG circulating in the bloodstream. Although these genetic variants only explain a small fraction of the sex hormone variability seen between individuals, they could provide insight into the diseases connected to sex hormone regulation.
The results showed that the SNPs that influence SHBG levels are near genes related to liver function, fat and carbohydrate metabolism and type 2 diabetes. In addition, there were genes that had stronger effects in one sex compared to the other.
‘These findings highlight the diverse range of biological processes that may be impacted by sex hormone regulation,’ said Dr. John Perry of the Peninsula College of Medicine and Dentistry, University of Exeter. EurekAlert
Olympic Team GB trials gene tests for injury
, /in E-News /by 3wmediaScientists behind Olympic Team GB are working on genetic tests to understand why some athletes are prone to injury, BBC’s Newsnight has learned.
Tendon injuries and stress fractures are common in elite athletes, but how and why they happen is less clear.
University College London’s Prof Hugh Montgomery says they have found a gene they think strongly influences the risk of stress fracture and more will come.
It is hoped the research will allow training to be individually tailored.
Diet, repetitive strain and loading are all known to play a part, and scientists say there is clearly a strong genetic element.
Director of the Institute for Human Health and Performance at University College London, Prof Montgomery carried out groundbreaking work on genes and fitness in the 1990s, most notably the ‘ACE’ gene, thought to be linked to endurance.
‘If we understood that genetic component we would have a much better understanding of the patho-physiology – the disease processes that let that happen,’ says Prof Montgomery.
He has been working closely with the English Institute of Sport (EIS), which aims to apply the latest in sports science and medicine for the benefit of Britain’s Olympic and Paralympic athletes.
EIS’s Director of Sport Science, Dr Ken van Someren, told Newsnight he is keen to apply the latest genetics discoveries.
‘If we can identify some particular genes that are associated with a higher risk of injury in certain individuals, and we think we’re close, we can tailor the training, conditioning and preparation that we put those individuals through.’
He added that should injury occur, the research could also influence the medical treatment the person receives.
But Dr van Someren stressed that there is no intention to use genes as a means of identifying sporting talent.
He says that for many people sport is about a fun and healthy lifestyle and genetics should not be used to screen people in or out of sport, adding that although genes might tell us a lot about the likelihood or probability of success, it is not an absolute science and there would be a danger of ‘missing out on some future champions.’
Prof Montgomery believes that looking for tomorrow’s sporting champions should involve looking at a combination of genes and the environment, rather than just relying on screening the genome.
He says we should look a person’s performance and dedication and to the sport rather than trying to ‘predict that dedication and performance by gene screening.’ BBC