Author Interviews, Brain Cancer - Brain Tumors, Genetic Research, Pediatrics, University of Pennsylvania / 04.02.2016

MedicalResearch.com Interview with: Dr. Adam C. Resnick, Ph.D Assistant Professor of Neurosurgery Faculty, Abramson Cancer Center Director of Children's Brain Tumor Tissue Consortium Division of Neurosurgery Director, CHOP/PENN Department of Neurosurgery Brain Tumor Tissue BiorepositoryDirector for Neurosurgical Translational Research, Division of Neurosurgery Children's Hospital of Philadelphia   Payal Jain, PhD Candidate Division of Neurosurgery, Children's Hospital of Philadelphia Department of Neurosurgery Cell and Molecular Biology Graduate Group Gene Therapy and Vaccines Program Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania   Medical Research: What is the background for this study? What are the main findings? Response: This study originates from our long-standing interest in studying pediatric low-grade gliomas (PLGGs), which are the most commonly diagnosed brain tumor in children. While several PLGGs have been found to harbor mutations/gene fusions driving the mitogen-associated protein kinase (MAPK) pathway leading to clinical trials testing MAPK inhibitors, these tumors remain poorly categorized and not enough is known about specific genetic mutations driving different tumor sub-types and the potential for specific targeted therapeutics. Our current study encompasses analysis of the largest combined genomic dataset of pediatric low-grade gliomas samples.  In doing this we, identified the MYB-QKI gene fusion, a non-MAPK related event, as the common genetic event driving a rare PLGG sub-type, called angiocentric gliomas. We have reported a novel tri-partite mechanism by which MYB-QKI mediates its oncogenic effect, this being the first report of a single gene rearrangement utilizing three different paths to cause cancer.
  • First, this gene rearrangement activates MYB, which is a proto-oncogene that is normally not expressed in the developed brain.
  • Second, we found that the rearrangement leads to translocation of QKI-related enhancers close to MYB’s promoters, thereby driving MYB-QKI expression in these tumors. Furthermore, MYB-QKI can also regulate its expression in a positive feedback loop.
  • Third, the tumor suppressor activities of QKI are disrupted in MYB-QKI. Such collaboration of genetic and epigenetic dysregulation in a single genetic rearrangement has previously not been reported.
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Author Interviews, Autism, Genetic Research, JAMA, Schizophrenia / 30.01.2016

MedicalResearch.com Interview with: Andrea J. Gonzalez-Mantilla, M.D. Postdoctoral Fellow Andres Moreno-De-Luca, M.D. Investigator I Autism & Developmental Medicine Institute Department of Radiology Geisinger Health System Danville, PA 17822 Medical Research: What is the background for this study? What are the main findings? Response: Developmental brain disorders (DBD), such as autism, intellectual disability, and schizophrenia are a group of heterogeneous conditions characterized by deficits that affect multiple functional domains, such as cognition, behavior, communication, and motor skills. Previous studies provide strong evidence of common underlying molecular pathways and shared genetic causes among apparently different DBDs. Large-scale genomic studies of individuals with developmental brain disorders have found that identifying multiple, independent de novo pathogenic loss-of-function (pLOF) variants in the same gene among unrelated individuals is a powerful statistical approach to reliably identify disease-causing genes. However, genomic data from smaller cohorts and case reports are not routinely pooled with data from larger studies. Moreover, most previous studies have been restricted to cohorts of individuals ascertained based on a single diagnosis (e.g., a study will focus on only individuals with a diagnosis of autism and not consider other genomic data from individuals with a different diagnosis). Therefore, genomic data from individuals across DBD are not being jointly analyzed in search of pLOF variants in the same gene that may help build evidence for a causative role in developmental brain disorders. In this study, we carried out data mining of previously published data to identify genes related to the DBD phenotype. We expanded the aforementioned method and developed a multilevel data-integration approach, which capitalizes on three genotype-phenotype data sources: (1) genomic data from structural and sequence pLOF variants, (2) phenotype data from six apparently distinct DBD (autism, intellectual disability, epilepsy, schizophrenia, bipolar disorder and attention-deficit/hyperactivity disorder), and (3) data from large scale studies, smaller cohorts, and case reports. We identified 241 candidate genes for developmental brain disorders, including 17 genes that had not previously been associated with developmental brain disorders. (more…)
Author Interviews, Cancer Research, Genetic Research, PNAS / 28.01.2016

MedicalResearch.com Interview with: Nina Bhardwaj, MD, PhD and Director of Immunotherapy and professor of Hematology and Medical Oncology Benjamin Greenbaum, PhD Assistant Professor The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai   Medical Research: How did the discovery of the group of non-coding RNA molecules in cancer cells that sets off an immune response come about? Dr. Greenbaum: Our work is a collaboration between my lab, which is computational, and the Bhardwaj lab, focused on cancer immunology. I had previously made the observation that certain RNA viruses were avoiding certain motifs, such as CpG dinucleotide containing motifs, and the Bhardwaj lab tested whether those motifs could set off an immune response. Recent work had shown that tumors transcribe unusual RNA with immunological consequences, so we investigated whether the same sort of approaches we had used for viral RNA worked here. Dr. Bhardwaj: It has recently become clear that, due to epigenetic alterations, tumors transcribe non-coding RNAs that are typically silenced. Often such RNA emanates from the “dark matter” genome. Many of these regions consist of repetitive elements and endogenous retroelements that are rarely transcribed in normal tissue. At the same time, due to immunotherapy, understanding the role of the immune system and immune activation in tumors has become critically important. The activation of specific elements of the innate immune system in a tumor may have either beneficial or detrimental effects for patients. Moreover, recent work has suggested that endogenous element activation can lead to improved immunotherapy outcomes. Therefore, it is critically important to understand the nature of innate immune activation in tumors and what triggers are responsible for these responses. We have been developing methods to detect abnormal patterns in viral RNA that may indicate activation of the innate immune system. We have found that patterns of motif usage avoided in the evolution of viruses, such as influenza, indicate RNA features that provoke an innate immune response. The innate immune system is capable of sensing motifs in viruses. We tested directly whether these avoided patterns are immunostimulatory. Medical Research: What are the main findings? Dr. Bhardwaj: We used a novel quantitative approach, derived from methods in statistical physics, to characterize all of the non-coding RNA transcribed by normal tissue and compared them to the non-coding RNA found in tumors. We found that while the non-coding RNA transcribed in normal tissue displays patterns of motif usage consisting with that of coding RNA, the RNA transcribed in tumors, yet rarely found in normal tissue, can have motif usage more typically associated with viral and bacterial genomes. We predicted a handful of such RNA are immunostimulatory and validated this prediction in antigen presenting cells. We then showed that this sensing may come from a subset of the innate immune system associated with pathogen RNA sensing. We called these RNA “i-ncRNA”, for immunostimulatory non-coding RNA. (more…)
Author Interviews, Duke, Genetic Research, Infections / 24.01.2016

MedicalResearch.com Interview with: Ephraim L. Tsalik, MD MHS PhD Assistant Professor of Medicine Division of Infectious Diseases Center for Applied Genomics & Precision Medicine Duke University Medical Center Emergency Department Service Line Durham VA Medical Center  Medical Research: What is the background for this study? What are the main findings? Dr. Tsalik: This study was motivated by the convergence of two research interests.  The first was spearheaded by Dr. Sack, leading our collaboration at Johns Hopkins.  Dr. Sack and his colleagues have a long history and expertise in studying enteric infections such as E. coli.  The second is our group here at Duke’s Center for Applied Genomics & Precision Medicine as well as the Durham VA Medical Center.  Specifically, we have an interest in studying the host response to infectious disease.  One of the ways we’ve done that historically is through challenge studies where healthy volunteers are exposed to a pathogen in a controlled setting.  Despite everyone getting the same exposure, not everyone gets sick.  That observation gives us a unique opportunity to study the host biology of symptomatic individuals, asymptomatic individuals, and what distinguishes the two from each other.  That is precisely what we did here. Volunteers ingested Enterotoxigenic E. coli (ETEC), which is a common cause of traveler’s diarrhea.  Some subjects became ill with diarrhea while others remained well.  In this study, we focused on gene expression patterns, which is a snapshot of how genes in the body are being used in response to this infection.  Some genes are more active, some are less.  The pattern of those changes that occur in response to infection is what we call a “signature”. This approach allowed us to generate some key findings.  First of all, we were able to define the genes involved in the body’s response to this type of E. coli infection.  Second, we discovered genes that were differentially expressed at baseline that could distinguish people who would go on to become ill from those that would remain healthy.  Although this study was not designed to identify the mechanism for that resilience to infection, it does focus our attention on where to look.  We suspect the genes we identified are likely to play a role in infectious disease resilience and susceptibility based on their known immune function roles.  We also have data, which wasn’t published in this study, that implicates some of these genes in the resilience to other infections such as influenza. The last major finding was something called Drug Repositioning Analysis.  This is a tool that allowed us to identify drugs and drug classes that could be used to mitigate infections caused by ETEC.  That analysis highlighted some compounds already known to be effective such as Zinc.  But it also identified several other drug classes that have not previously been investigated and could be important tools to combat such infections especially as antibiotic resistance looms. (more…)
Author Interviews, Breast Cancer, Genetic Research, NYU / 16.01.2016

More on Breast Cancer Research on MedicalResearch.com MedicalResearch.com Interview with: Dr. Benjamin Neel MD PhD Professor, Department of Medicine Director Perlmutter Cancer Center NYU Langone Medical Center Medical Research: What is the background for this study? What are the main findings? Dr. Neel:  Over the past 10 years, there have been major advances in cancer genomics--i.e., defining what changes in genes are found in different types of cancer cells.  Sometimes, such studies have resulted in the identification of new drug targets, such as EGF receptor mutations or EML-ALK translocations in lung cancer, RAF mutations in melanoma and hairy cell leukemia, and KIT or PDGFR mutations in GIST.  More often, though, either the genetic changes that genomic studies reveal are difficult to target by conventional small molecule drugs or we dont know which of the many mutations found in a given tumor are critical to its proliferation/survival. "Functional genomics" is a parallel approach to tumor genomics, that aims to use large scale screening technology to identify which genes are essential to cancer cell survival/proliferation.  This approach can reveal which genetic changes in cancer cells "drive" the cancer--but it also can find genes on which the cancer becomes dependent because of the other "driver" genes.  One major approach to functional genomics uses short hairpin RNAs (a type of RNAinterference/RNAi) to "knock down" the expression of each gene in a cell.  Scientists can generate a "library" of designer virus particles, each of which expresses a different hairpin that can "knockdown" a different gene.  A large population of tumor cells is then infected with the virus, and scientists use gene sequencing or array based approaches to see which shRNAs become depleted from the starting population of shRNAs; this type of screen is called a "dropout screen". Earlier studies, including by our group, performed dropout screens on smaller numbers of cancer cell lines.  Yet because these screens involved only a few cell lines, they could not represent the large number of sub-types knownt to occur in, for example, breast cancer.  Our study, by using 77 breast cancer lines, has adequate power to survey the landscape of breast cancer. Furthermore, by obtaining parallel genomic information, as well as some information on the breast cancer cell "proteome" (the proteins in these cells), we can couple genomic analysis with functional genomics. In addition, we had drug response information for a large number of these lines, and so were able to make some predictions for drugs that might prove additive for breast cancer therapy. The result is a large number of potential new targets linked to genetic information, as well as new insights into how the different sub-types of breast cancer "rewire" their respective signaling diagrams compared with normal cells. (more…)
Author Interviews, Genetic Research, UT Southwestern / 09.01.2016

MedicalResearch.com Interview with: Rhonda Bassel-Duby, Ph.D. and Dr. Chengzu Long, PhD Department of Molecular Biology UT Southwestern Medical Center Dallas, TX 75390-9148 Medical Research: What is the background for this study? What are the main findings? Response: Duchenne muscular dystrophy (DMD), which was first described by Duchenne de Boulogne (1806-1875) in 1860s, is one of the most severe and common type of muscular dystrophy. DMD is caused by mutations in the gene for dystrophin (DMD) on the X chromosome and affects approximately 1 in 3500 to 5000 boys. Without dystrophin, a large cytoskeletal protein, muscles degenerate, causing myopathy. Symptoms can be visible between 1 to 6 years old. Most Duchenne muscular dystrophy patients are confined to a wheelchair by age 12. Death of DMD patients usually occurs by age 25, typically from breathing complications and cardiomyopathy. Hence, therapy for  Duchenne muscular dystrophy necessitates sustained rescue of skeletal, respiratory and cardiac muscle structure and function. Although several gene therapies have been tested, there is no curative treatment so far. Duchenne muscular dystrophy arises from a monogenic mutations in dystrophin gene. This makes DMD an ideal disease model for CRISPR-mediated gene editing therapeutics, a major breakthrough in gene engineering in the past three years. This system can remove the defect within the gene. In 2014, in a first proof of concept study, Olson’s team used CRISPR-mediated gene editing to correct the dystrophin gene mutation in the germline of DMD mouse model. In this new paper, we advanced the same technology to postnatal muscle tissues by delivery gene editing components via a harmless adeno-associated virus. Skeletal and cardiac muscle showed progressive rescue of dystrophin protein. (more…)
Author Interviews, Cancer Research, Genetic Research, Personalized Medicine, Technology / 06.01.2016

MedicalResearch.com Interview with: Dr Bissan Al-Lazikani Team leader in computational biology The Institute of Cancer Research London Medical Research: What is the background for the canSAR database? What are the main uses for the tool? Dr. Al-Lazikani: Drug discovery is a difficult, time consuming and expensive venture that frequently ends in late stage drug failures - especially in oncology. As with any complex venture, decisions throughout the drug discovery pipeline can be empowered by having access to the right information at the right time. But for drug discovery this means bringing together billions of experimental data from very diverse areas of science spanning genomics, proteomics, chemistry and more. We developed canSAR to help guide our own drug discovery efforts by integrating these huge, diverse data and by analysing the data and deriving hidden links and knowledge from them. This means that we can answer questions in minutes that would have taken weeks using previously available public resources. But, more importantly, canSAR analyses and links these data in a way that allows us  to derive knowledge that was hidden before. For example, one of the main ways canSAR is used is to help select the best druggable targets for drug discovery. Using canSAR we were able to uncover many druggable cancer proteins that were previously overlooked, and we are delighted to see that several of these proteins are now the subjects of drug discovery and development projects both by us and by others. We took the decision to make canSAR publicly and freely available because we believe that cancer drug discovery is a vast challenge that requires openness and data sharing worldwide. It has been embraced by the community is being used by tens of thousands of cancer scientists worldwide, both in academia and industry, to generate hypotheses for experiments and select targets for drug discovery. (more…)
Author Interviews, Breast Cancer, Genetic Research, Journal Clinical Oncology / 23.12.2015

MedicalResearch.com Interview with: Dr. Marjanka Schmidt PhD Group Leader, Molecular Pathology Netherlands Cancer Institute Medical Research: What is the background for this study? What are the main findings? Dr. Schmidt: BRCA1/2 mutation carriers who developed a primary breast cancer are thought to be at high risk to develop a contralateral breast cancer (breast cancer in the opposite breast). Our study is one of the first to provide unbiased risk estimates for young breast cancer patients with a pathogenic BRCA1/2 mutation. We also showed that age of onset of the first breast cancer is a predictor for the development of contralateral breast cancer in BRCA1/2 mutation carriers, but not in non-carriers. (more…)
Author Interviews, Genetic Research, Immunotherapy / 22.12.2015

MedicalResearch.com Interview with: Benjamin Greenbaum, PhD Assistant Professor and Professor Nina Bhardwaj MD PhD Hematology and Medical Oncology Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York, NY 10029 Medical Research: What is the background for this study? Response: It has recently become clear that, due to epigenetic alterations, tumors transcribe non-coding RNAs that are typically silenced. Often such RNA emanates from the “dark matter” genome. Many of these regions consist of repetitive elements and endogenous retroelements that are rarely transcribed in normal tissue. At the same time, due to immunotherapy, understanding the role of the immune system and immune activation in tumors has become critically important. The activation of specific elements of the innate immune system in a tumor may have either beneficial or detrimental effects for patients. Moreover, recent work has suggested that endogenous element activation can lead to improved immunotherapy outcomes. Therefore, it is critically important to understand the nature of innate immune activation in tumors and what triggers are responsible for these responses. We have been developing methods to detect abnormal patterns in viral RNA that may indicate activation of the innate immune system. We have found that patterns of motif usage avoided in the evolution of viruses, such as influenza, indicate RNA features that provoke an innate immune response. The innate immune system is capable of sensing motifs in viruses. We tested directly whether these avoided patterns are immunostimulatory. (more…)
Author Interviews, Cancer Research, Genetic Research, Nature / 17.12.2015

MedicalResearch.com Interview with: Dr. Li Ding PhD Director, Medical Genomics group McDonnell Genome Institute Department of Medicine Washington University in St. Louis St. Louis, Missouri Medical Research: What is the background for this study? What are the main findings? Dr. Li Ding:  Next-generation sequencing technologies have provided unprecedented opportunities for building a comprehensive catalog of point mutations, simple insertion and deletion mutations (indels) and structural variants in human cancers. Although significant progress has been made for documenting these common events through studies from individual research labs and large consortiums, there has been little progress in the discovery of complex indels after the transition from Sanger sequencing to NGS technologies.  It is well known in the scientific community that indel detection using short next generation sequencing reads is a challenging problem. Our study, for the first time, directly addresses complex indel detection that has been barely touched in the cancer field. More importantly, our analysis discovered 285 complex indels in cancer genes such as PIK3R1, GATA3, and TP53, revealing an unexpected high prevalence of these events in human cancers. (more…)
Author Interviews, Genetic Research, Methamphetamine, PLoS / 16.12.2015

MedicalResearch.com Interview with: Camron D. Bryant, Ph.D. Assistant Professor Laboratory of Addiction Genetics Department of Pharmacology and Experimental Therapeutics & Psychiatry Boston University School of Medicine Boston, MA 02118  Medical Research: What is the background for this study? What are the main findings? Dr. Bryant: The addictions, including addiction to psychostimulants such as methamphetamine and cocaine, are heritable neuropsychiatric disorders. However, the genetic factors underlying these disorders are almost completely unknown. We used an unbiased, discovery-based genetic approach to fine map a novel candidate genetic factor influencing the acute stimulant response to methamphetamine in mice. We then directly validated the causal genetic factor using a gene editing approach. The gene - Hnrnph1 (heterogeneous nuclear ribonucleoprotein H1) - codes for an RNA binding protein that is involved in alternative splicing of hundreds of genes in the brain. Based on a genome-wide transcriptome analysis of differentially expressed genes within the striatum -  a crucial brain region involved in the stimulant properties of amphetamines - we predict that Hnrnph1 is essential for proper neural development of the dopamine circuitry in the brain. These findings could have implications for understanding not only the addictions but also other neuropsychiatric disordersthat involve perturbations in the dopaminergic circuitry. (e.g., ADHD and schizophrenia) as well as neurodegenerative disorders such as Parkinson's disease. (more…)
Author Interviews, Dermatology, Genetic Research, JAMA, Melanoma / 10.12.2015

MedicalResearch.com Interview with: Susana Puig MD PhD Chief Dermatology Service Research Director "Melanoma: Imaging, genetics and immunology" at IDIBAPS Consultant & Assistant Professor Melanoma Unit, Dermatology Department Hospital Clinic, University of Barcelona Barcelona Spain  Medical Research: What is the background for this study? What are the main findings? Dr. Puig: CDKN2A is the main high-penetrance melanoma susceptibility gene. A rare functional variant in MITF, p.E318K (rs149617956), has been identified as a moderate risk allele in melanoma susceptibility and also predisposes to renal cell carcinoma. In this study MITF p.E318K was associated with an increased melanoma risk (OR=3.3, p<0.01), especially in patients with multiple primary melanoma (OR=4.5, p<0.01) and high nevi count (>200 nevi) (OR=8.4, p<0.01). Interestingly, two fast growing melanomas were detected among two MITF p.E318K carriers during dermatologic digital follow-up. Furthermore, we have detected a similar prevalence of MITF p.E318K in CDKN2A wild-type and mutated individuals. (more…)
Author Interviews, Breast Cancer, Cancer, Genetic Research / 07.12.2015

MedicalResearch.com Interview with: Dr. Jane E. Churpek, MD Assistant Professor of Medicine Co-Director, Comprehensive Cancer Risk and Prevention Program The University of Chicago Medicine Chicago, IL 6063 Medical Research: What is the background for this study? What are the main findings? Dr. Churpek:   We designed this study to try to understand whether damaging, inherited changes in genes known to cause an increased risk of breast cancer are common in those who develop leukemia after getting chemotherapy and/or radiation for treatment of breast cancer. Leukemias that occur in this setting are called “therapy-related.” This means that chemotherapy or radiation, or both, may have been involved in causing the leukemia.  This is an uncommon but serious complication of cancer treatment, and the factors that put women at risk for this complication are not well understood. We looked at the clinical histories of 88 such women. We found that most of them have relatives who also had cancer, suggesting they may be cancer-prone to begin with. Because we did not have a group of women who had similar breast cancer treatment and who did not get a therapy-related leukemia, we cannot definitively prove that more women with therapy-related leukemia than expected had these mutations. However, this study gives us reason to further study the role of these genes in therapy-related leukemia. (more…)
Author Interviews, Genetic Research, Weight Research / 06.12.2015

MedicalResearch.com Interview with: Ida Donkin MD, PhD Postdoc, Medical Doctor, PhD University of Copenhagen Faculty Of Health Sciences Copenhagen, Denmark Medical Research: What is the background for this study? Dr. Donkin: We know that children of obese fathers are more prone to develop obesity themselves – regardless of the weight of the mother. We also know that obesity and diabetes are diseases with a very big inheritable components in their aetiology. If your parents are obese, you have a risk of about 75% percent of developing obesity yourself. But we do not know how the disease is inherited from one generation to the next. Despite exhaustive research trying to investigate genes potentially responsible for this, and more than 125 genetic mutations have been discovered to associate to the development of obesity, all the genetic mutations put together cannot explain more than about 10% of the actual inheritance. So how is obesity inherited from parents to children? One explanation could be the transfer of epigenetic information from one generation to the next. Epigenetic information is established in our body’s cells in response to our lifestyle and the environment around us. We discovered that the epigenetic factors of semen cells also responds to changes in our lifestyle, and we speculated whether these might be the key to understand how obesity in dads can lead to obesity in children. Medical Research: What are the main findings? Dr. Donkin: In this study we discovered that the information kept in our semen cells responds dynamically to changes in our lifestyle. If you are obese, your semen cells will contain a different epigenetic pattern than if you are lean. Weight loss induced by gastric bypass surgery will dynamically change these epigenetic patterns, meaning that by changing our lifestyle, we can actively change the epigenetic information we pass on to our children. Other research groups have created solid evidence showing us that most these epigenetic marks kept in the sperm cells will be passed on to the embryo at fertilization. The epigenetic information can affect the development of the embryo, and thereby change the health – and the risk of disease – of our children. Our study thus provides a likely explanation for the mechanism of the inheritance of acquired traits and diseases through generations, and gives us a likely explanation as to why children of obese fathers are more prone to develop obesity themselves. (more…)
Author Interviews, Genetic Research, Heart Disease, Neurological Disorders, NIH, Science / 05.12.2015

MedicalResearch.com Interview with: Jonathan Kaltman, MD Chief, Heart Development and Structural Diseases Branch Division of Cardiovascular Sciences National Heart, Lung, and Blood Institute Medical Research: What are the main findings? Dr. Kaltman:  Congenital heart disease (CHD) is the most common birth defect but the cause for most defects is unknown.  Surgery and clinical care of patients with congenital heart disease has improved survival but now we are learning that many patients have neurodevelopmental abnormalities, including learning disability and attention/behavioral issues. Medical Research:  What are the main findings?
  • Using exome sequencing we found that patients with  congenital heart disease have a substantial number of de novo mutations.  This finding is especially strong in patients with CHD and another structural birth defect and/or neurodevelopmental abnormalities.
  • Many of the genes identified are known to be expressed in both the heart and the brain, suggesting a single mutation may contribute to both congenital heart disease and neurodevelopmental abnormalities.
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Author Interviews, BMC, BMJ, Genetic Research / 03.12.2015

MedicalResearch.com Interview with: Hatem A. Azim MD PhD Breast Cancer Translational Research Laboratory Institut Jules Bordet Université Libre de Bruxelles Brussels, Belgium Medical Research: What is the background for this study? What are the main findings? Dr. Azim: As at breast cancer diagnosis is known to impact prognosis, with young patients having worse outcome. On the other hand, elderly patients are less studies in general and little is known on their tumor characteristics. In this study, we aimed to define the pattern of genomic aberrations in different age groups. This can result in identifying if key potentially targetable genomic alterations are more specific to particular age groups and thus could open the door to design particular studies targeting these aberrations in these age groups. We found that  age is associated with unique biological features at the DNA level, independent of tumor stage, histology and breast cancer molecular subtype. Of particular mention, the higher prevalence of GATA3 mutation in younger patient, a known driver mutation associated with endocrine resistance. In addition, age at diagnosis appears to impact the tumor transcriptome confirming previous observations, but also highlighting novel findings, of particular relevance the higher expression of stem cell related genes in young patients. (more…)
Author Interviews, Genetic Research, Pediatrics / 25.11.2015

MedicalResearch.com Interview Grant S Schulert MD, PhD Clinical Fellow, Division of Rheumatology Cincinnati Childrens Hospital  Medical Research: What is the background for this study? What are the main findings? Dr. Schulert: Influenza infection causes millions of illnesses annually, but most of those are relatively mild.  In a subset of cases, patients can become critically ill, even if they are relatively young and healthy.  Several previous reports had observed in these critically ill patients features of a hyperinflammatory syndrome known as HLH (hemophagocytic lymphohistiocytosis) or MAS (macrophage activation syndrome).  This hyperinflammation can be triggered by other infections as well as in a subtype of juvenile arthritis, but there is also a familial form occurring in early childhood with known genetic causes.  Our questions with this study were 1) how often are features consistent with HLH/MAS seen in fatal H1N1 influenza infections and 2) do patients with fatal H1N1 infection have genetic mutations associated with HLH/MAS? Our collaborator Paul Harms, MD, and his team at the Michigan Center for Translational Pathology, University of Michigan Medical School identified 16 cases of fatal H1N1 influenza infection.  Based on their clinical features, between 41-88% of these patients could be categorized as having a hyperinflammatory HLH/MAS.  We then used processed tissue samples from the patients for whole exome genetic sequencing, which reads the entire genetic code of every gene in a person. Five patients carried mutations in genes which cause HLH, and several others carried mutations in genes linked to MAS.  This suggests that there may be genetic risk factors for developing fatal hyperinflammatory syndromes in H1N1 infection. (more…)
Author Interviews, Critical Care - Intensive Care - ICUs, Genetic Research, Pulmonary Disease / 20.11.2015

MedicalResearch.com Interview with: Dragana Vidovic and Marianne Carlon Laboratory for Molecular Virology and Gene Therapy KU Leuven, Belgium Medical Research: What is the background for this study? What are the main findings? Response: Cystic fibrosis (CF) or mucoviscidosis is a genetic disorder caused by mutations in the CFTR gene which codes for a chloride/bicarbonate channel that regulates fluid secretion across the epithelium in different organs, for instance, the airways and the gastrointestinal tract. In the cells of CF patients, these anion channels are dysfunctional or even absent leading to the formation of sticky mucus. Persistent airway infection is the major clinical manifestation. The symptoms can be treated, but there is no cure for the disorder. Gene therapy holds promise to cure the disease. Previous studies suggested that the treatment is safe, but largely ineffective for Cystic fibrosis patients. However, as gene therapy has recently proven successful for inherited disorders such as haemophilia and congenital blindness, we wanted to re-examine its potential for CF. Here we developed an improved gene therapy treatment based on inserting the CFTR gene into the genome of a recombinant AAV viral vector (rAAV), which is derived from the relatively innocent AAV virus. We used this vector to “smuggle” a healthy copy of the CFTR gene into the affected cells. We administered rAAV to CF mice via their airways. Most of the mice recovered. In patient-derived intestinal cell cultures or organoids, chloride and fluid transport was restored. Medical Research: What does the study add to the field? Response: Development of Cystic fibrosis gene therapy requires a thorough preclinical examination of a candidate vector in relevant cell and animal models before being administered to humans. Here, both in mice with Cystic fibrosis and in mini-guts or intestinal organoids derived from Cystic fibrosis patients, this approach yielded positive results setting the stage for further validation in large animal models which mimic the CF patient situation more faithfully. We believe that our study will revive the interest in CF gene therapy as a promising, mutation-independent approach to ultimately cure Cystic fibrosis. (more…)
Author Interviews, Genetic Research, JAMA, Neurological Disorders / 17.11.2015

MedicalResearch.com Interview with: Kevin M. Biglan, M.D., M.P.H Professor of Neurology and the Associate Chair for Clinical Research Department of Neurology and the Center for Human Experimental Therapeutics University of Rochester School of Medicine and Dentistry Rochester, New York  Medical Research: What is the background for this study? What are the main findings? Dr. Biglan: A therapeutic goal of research in Huntington Disease (HD) is the identification of treatments that delay the progression of disease and onset of illness in individuals at risk for developing manifest HD. Designing such efficacy trials is challenging. A major hurdle is the lack of practical primary outcome measures to assess the effect of an intervention on delaying disease onset. Use of the dichotomous endpoint of clinical diagnosis as the primary outcome requires large sample sizes and long duration of follow up in order to show a significant therapeutic effect on delaying disease onset. Continuous measures that can reliably distinguish cytosine-adenine-guanine (CAG) expanded individuals in the pre-manifest period may allow for the identification of potential disease modifying therapies using relatively smaller cohorts followed for shorter periods of time. The Prospective Huntington At-Risk Observational Study (PHAROS) represents the largest observational study to clinically evaluate pre-manifest Huntington Disease wherein both research participants and investigators were unaware of Huntington Disease mutation status. Accordingly, PHAROS was uniquely designed to address, in an unbiased manner, those clinical features most associated with the CAG expansion during the prodromal phase in  Huntington Disease.  The identification of continuous outcome measures that are associated with HD in the pre-manifest period may facilitate the design and powering of future studies of potential disease modifying therapies prior to traditional motor diagnosis. (more…)
Author Interviews, Cancer Research, Genetic Research, JAMA / 14.11.2015

MedicalResearch.com Interview with: Samuel Klempner, M.D. Assistant Professor Division of Hematology/Oncology UC Irvine Health Orange, CA 92868  Medical Research: What is the background for this study? What are the main findings? Dr. Klempner: The background for our series is the concept that little is known about the genetic landscape of rare tumors such as acinic cell tumors, and that understanding genetic changes in tumors can identify treatment options.  This paradigm can, and should, be extended beyond rare tumor types and many researchers are currently studying various tumor types.  Another important background idea is that tumor genomic alterations may be more important than that anatomic site of origin. For example, I would argue that a breast cancer that harbors an EGFR mutation common to lung cancer could be treated similar to a lung cancer based on the genomic changes. In our study we found another way that the BRAF protein and its downstream signaling may become activated through duplicating part of the protein called the kinase domain.  This genetic event causes the pathway to be always "on" which is not normal, and likely drives cancer growth.  However, BRAF kinase domain duplication appears sensitive to currently available drugs that target the BRAF pathway, as evidenced by the response in our patient.  Thus, finding this change is important and may be able to guide a more personalized therapy choice.  Importantly, we found BRAF kinase domain duplication across multiple different tumor types, suggesting this may be a recurrent event in some cancers.  A very similar finding, involving duplication of the EGFR kinase domain, was also just reported (Cancer Discovery 2015;5:1155-1163) lending further validation to this mechanism of pathway activation in cancer. (more…)
Author Interviews, Dermatology, Melanoma, NEJM, UCSF / 13.11.2015

MedicalResearch.com Interview with: Boris C. Bastian, MD, PhD Professor of Dermatology and Pathology Gerson and Barbara Bass Bakar Distinguished Professor in Cancer Research University of California, San Francisco Medical Research: What is the background for this study? What are the main findings? Dr. Bastian:  The cost of DNA sequencing has dropped substantially since the initial sequencing of the human genome in 2001. As a result, the most common cancer subtypes have now been sequenced, revealing the pathogenic mutations that drive them. A typical cancer is driven by 5-10 mutations, but we still do not understand the order in which these mutations occur for most cancers. Determining the order in which mutations occur is challenging for cancers that are detected at a late stage. Melanomas, however, lend themselves to this type of analysis because they are pigmented and found on the surface of the skin, allowing them to be identified early. Sometimes, melanomas are even found adjacent to their remnant precursor neoplasms, such as benign nevi (also known as common moles). We performed detailed genetic analyses of 37 cases of melanomas that were adjacent to their intact precursor neoplasms. We microdissected and sequenced the surrounding uninvolved normal tissue, the precursor neoplasm, and the descendent neoplasm. By comparing the genetic abnormalities in each of the microdissected areas, we were able to decipher the order of genetic alterations for each case. Our work reveals the stereotypic pattern of mutations as they occur in melanoma. Mutations in the MAPK pathway, usually affecting BRAF or NRAS, occur earliest, followed by TERT promoter mutations, then CDKN2Aalterations, and finally TP53 and PTEN alterations. Benign nevi typically harbor a single pathogenic alteration, whereas fully evolved melanomas harbor three or more pathogenic alterations. We also identified an intermediate stage of neoplasia with some but not all of the pathogenic mutations required for fully evolved melanoma. There has been a longstanding debate whether morphologically intermediate lesions, such as dysplastic nevi, truly constitute biological intermediates or whether they simply represent a gray zone of histopathological assessment. Our data indicates that these neoplasms are genuine biological entities. Finally, we observe evidence of UV-radiation-induced DNA damage at all stages of pathogenesis, implicating UV radiation in both the initiation and progression of melanoma. (more…)
Author Interviews, Genetic Research, Race/Ethnic Diversity, Weight Research / 06.11.2015

MedicalResearch.com Interview with: Joan C. Han, MD Director, Pediatric Obesity Program, Le Bonheur Children’s Hospital Associate Professor, Division of Pediatric Endocrinology Department of Pediatrics, University of Tennessee Health Science Center Memphis, TN 38103 Medical Research: What is the background for this study? What are the main findings? Dr. Han: Obesity has become a world-wide epidemic. Our research group studies the genetic factors that contribute to the development of obesity. Brain-derived neurotrophic factor (BDNF) is a protein that plays a key role in regulating appetite. We found that a common genetic variant of the BDNF gene is associated with lower expression of this gene in the hypothalamus, a region of the brain that controls energy balance. The mechanism of this reduced gene expression appears to be due to diminished binding of the transcription factor hnRNPD0B. We also observed that this genetic variant is associated with higher body mass index and higher body fat in children and adults. The obesity-predisposing variant of the BDNF gene occurs more commonly in people of African-American or Hispanic backgrounds, which could have important clinical implications given the higher rates of obesity in these populations. (more…)
Author Interviews, Geriatrics, Infections / 28.10.2015

MedicalResearch.com Interview with: Christian Hammer, PhD École Polytechnique Fédérale de Lausanne Swiss Institute of Bioinformatics Lausanne, Switzerland Clinical Neuroscience Max Planck Institute of Experimental Medicine Göttingen, Germany Medical Research: What is the background for this study? What are the main findings? Dr. Hammer: The immune response after viral infection or vaccination varies considerably from person to person, which is important because these differences can account for clinical outcome or vaccine effectiveness. It has been shown before that part of this variability is heritable, indicating the possibility that differences in our genes might be involved. To test this, we performed a genome-wide association study in more than 2,300 individuals, using high-performance computing to analyze whether differences in the abundance of antibodies against 14 common viruses are caused by variable sites in our genome. We looked at about 6 million of these variants and found that a region on chromosome 6 that harbors many genes involved in immune regulation showed highly significant associations with immune response to influenza A virus, Epstein-Barr virus (EBV), JC polyomavirus, and Merkel Cell polyomavirus. The genetic variants result in structural differences in proteins whose job it is to present fragments of pathogens that have been taken up by cells to the immune system. Interestingly, a given variant can lead to an increased immune response to one virus, e.g. influenza A, and at the same time to a decreased immune response to another, e.g. EBV, which is likely due to an altered ability of the protein to bind and present specific viruses, depending on the genetic background. (more…)
Author Interviews, Genetic Research, Kidney Disease, Nature, Stem Cells / 24.10.2015

MedicalResearch.com Interview with: Benjamin Freedman, Ph.D. Assistant Professor | University of Washington Department of Medicine | Division of Nephrology Member, Kidney Research Institute Member, Institute for Stem Cell and Regenerative Medicine Seattle WA 98109  Medical Research: What is the background for this study? What are the main findings? Dr. Freedman: We are born with a limited number of kidney tubular subunits called nephrons. There are many different types of kidney disease that affect different parts of the nephron. The common denominator between all of these diseases is the irreversible loss of nephrons, which causes chronic kidney disease in 730 million patients worldwide, and end stage renal disease in 2.5 million. Few treatments have been discovered that specifically treat kidney disease, and the therapeutic gold standards, dialysis and transplant, are of limited availability and efficacy. Pluripotent stem cells are a renewable source of patient-specific human tissues for regeneration and disease analysis. In our study, we investigated the potential of pluripotent cells to re-create functional kidney tissue and disease in the lab. Pluripotent cells treated with a simple chemical cocktail matured into mini-kidney 'organoids' that closely resembled nephrons. Using an advanced gene editing technique called CRISPR, we created stem cells with genetic mutations linked to two common kidney diseases, polycystic kidney disease (PKD) and glomerulonephritis. Mini-kidneys derived from these genetically engineered cells showed specific 'symptoms' of these two different diseases in the petri dish. (more…)
Author Interviews, Genetic Research, Lancet, Macular Degeneration, Ophthalmology / 12.10.2015

Professor P. Elizabeth Rakoczy Centre for Ophthalmology and Visual Sciences The University of Western Australia Head of Department - Molecular Ophthalmology Lions Eye Institute AustraliaMedicalResearch.com Interview with: Professor  P. Elizabeth Rakoczy Centre for Ophthalmology and Visual Sciences The University of Western Australia Head of Department - Molecular Ophthalmology Lions Eye Institute Australia Medical Research: What is the background for this study? Prof. Rakoczy: Wet age related macular (wet-AMD) is the major cause of blindness in the developed world. It is treated with frequent anti-VEGF injections into the eye. Our preclinical studies demonstrated that following the subretinal injection of a recombinant adeno-associated vector (rAAV) carrying a natural inhibitor of neovascularization (sFlt-1), leaky new, abnormal vessels can be controlled and retinal anatomy improved. The rAAV.sFlt-1 based Ocular Biofactory™ platform has potentially significant advantages over existing technologies as it is designed to provide sustained production of a naturally occurring antiangiogenic agent, sFlt-1, in situ in the eye. In this trial we investigated the safety of rAAV.sFlt-1 in patients diagnosed with wet-AMD. (more…)
Author Interviews, Fertility, Genetic Research / 09.10.2015

Rajiv McCoy, PhD Dept. of Genome Sciences Univ. of WashingtonMedicalResearch.com Interview with: Rajiv McCoy, PhD Dept. of Genome Sciences Univ. of Washington Medical Research: What is the background for this study? What are the main findings? Dr. McCoy:  Aneuploidy—the inheritance of extra or missing chromosomes compared to the typical 46-chromosome set—is extremely common in human embryos. The vast majority of aneuploidies result in preclinical pregnancy loss, often before the pregnancy is even recognized by the mother. This is thought to be the primary reason why only ~30% of all conceptions result in successful live birth. Many aneuploidies arise during egg formation, with the frequency increasing with maternal age. In addition to meiotic errors, a large proportion of aneuploidies affecting cleavage-stage embryos are mitotic in origin, arising during the initial post-fertilization cell divisions. These initial divisions are controlled by machinery contributed by the mother in the egg (before the embryo's genome has been activated). While these mitotic errors are frequent in cleavage-stage embryos, we found that they are rare in embryos at day-5 of development (the blastocyst stage), suggesting that embryos and/or cells with extensive mitotic errors do not survive to day 5. We discovered that some women have a greater propensity to produce embryos with mitotic errors than others, and our idea was that maybe differences in the mitotic machinery could help explain this. Using data from in vitro fertilized embryos screened by our collaborators at Natera, we found that women who have a particular version of a gene called PLK4 tend to produce more aneuploid embryos, regardless of age. This genetic variant is actually very common—more than half of people carry at least one copy—and is present in nearly all populations. PLK4 has a well-known role in ensuring the proper distribution of chromosomes. We also found that patients referred for embryo screening due to previous IVF failure had higher rates of mitotic error, which underscores the clinical importance of this form of whole-chromosome abnormality. (more…)
Author Interviews, Genetic Research, Lung Cancer, PLoS / 07.10.2015

MedicalResearch.com Interview with: Keiji Tanimoto, D.D.S., Ph.D Assistant Professor Research Institute for Radiation Biology and Medicine Hiroshima University Hiroshima Japan Medical Research: What is the background for this study? Dr. Tanimoto: Hypoxia-inducible factor-2α (HIF-2αor EPAS1) is important for cancer progression, and its overexpression is considered a putative biomarker for poor prognosis in patients with lung cancer. However, molecular mechanisms underlying EPAS1 overexpression are not fully understood. Recently, several SNPs of EPAS1 have been reported to be associated with the development of various diseases including cancer. Therefore, we focused on SNPs within EPAS1, and examined the roles of these SNPs in regulation of EPAS1 gene expression and the association of these SNPs with prognosis of non-small cell lung cancer (NSCLC) patients by bioinformatics analyses. Medical Research: What are the main findings? Dr. Tanimoto:
  • The SNP within the EPAS1 intron 1 region (rs13419896) may affect EPAS1 gene and protein expression;
  • The fragment with A allele of the SNP showed higher transactivation activity than one with G, especially in the presence of overexpressed c-Fos or c-Jun;
  • The median survival time of NSCLC patients with at least one A allele of rs13419896 was significantly shorter than that with the G/G homozygote (28.0 vs. 52.5 months, P = 0.047, log-rank test);
  • The possession of A allele of rs13419896, along with clinical stage, was an independent variable for risk estimation of overall survival for NSCLC patients [hazard ratio (HR) = 2.31, 95% CI = 1.14-4.81, P = 0.021], after adjustment for age, gender, stage, histology, tumor size, and differentiation.
(more…)
Author Interviews, Personalized Medicine, Transplantation, University of Pennsylvania / 05.10.2015

MedicalResearch.com Interview with: Brendan J. Keating, DPhil Assistant professor of Transplant Surgery Penn Medicine Medical Research: What is the background for this study? What are the main findings? Response: Genetic studies in transplantation have been plagued by small samples and very complex phenotypes/outcomes of patients. Transplanted individuals are typically on potent immunosuppression drugs for the rest of their lives, as they have 3.5 million to 10 million variants difference from an unrelated transplanted donor organ. Such populations would certainly benefit from large well-powered genetic studies but only 3 transplant genome-wide genotyping studies comprising a few hundred individuals have been published. The papers outline the resources in hand for the International Genetics & Translational Research in Transplantation Network, comprising 22 studies to date (since the publication it has now expanded to 25 studies and > 32,000 subjects with genome-wide genotyping data). We show significant statistical power in iGeneTRAiN to detect main effect association signals across regions such as the MHC region (which harbors the HLA Class I/II regions which are well established to associate with transplantation outcomes). We also show strong genome-wide power to detect transplant outcomes that span all solid organs including graft survival, acute rejection, new onset of diabetes after transplantation (fast becoming the most common comorbidity post-transplantation), and delayed graft function (to date we have looked at this in kidney transplant patients only). We show that iGeneTRAiN is statistically powered to deliver pioneering insights into the genetic architecture of transplant-related outcomes across a range of different solid-organ transplant studies. The transplant specific GWAS array that we designed (described in depth in the Genome Medicine paper) show that the coverage in key transplant associated regions is much higher than conventional arrays, and we describe the ‘imputation’ pipeline to expand the 780,000 or so variants examined in any given individual to > 15 millions of variants using whole genome sequencing reference datasets. (more…)
Author Interviews, Genetic Research, Nutrition, Weight Research / 05.10.2015

Jacqueline Alvarez-Leite MD, Ph.D Full Professor, UFMG Moore Laboratory Massachusetts General HospitalMedicalResearch.com Interview with: Jacqueline Alvarez-Leite  MD, Ph.D Federal University of Minas Gerias in Brazil Medical Research: What is the background for this study? What are the main findings? Dr. Alvarez-Leite : Obesity is now a global epidemic and bariatric surgery is now the main therapeutic option for those individuals with extreme obesity in which clinical treatments failed. However, a significant proportion of those patients regain the weight lost 3-4 years after surgery. Therefore, some metabolic or genetic trait may be related to weight regain. The rs9939609 single nucleotide polymorphism (SNP) in the fat mass and obesity- associated (FTO) gene is one of the most studied genes involved in obesity. However, few studies have been conducted on patients who underwent bariatric surgery. In our study, we evaluated the influence of  this FTO SNP on body weight and composition, and weight regain in 146 patients during a 60-mo follow-up period after bariatric surgery. We observed that there was a different evolution of weight loss in individual with obesity carriers of the FTO gene variant after bariatric surgery. However, this pattern is evident at only 2 y post bariatric
 surgery, inducing a lower proportion of surgery success (percentage of excess weight loss >50%) and greater and earlier weight regain after 3-y of follow-up. Multiple regression 
analyses showed that the variation in rs9939609 was a significant and independent predictor for regaining weight during the 
5-y follow-up period. (more…)
Author Interviews, Breast Cancer, Chemotherapy, Genetic Research, NEJM / 29.09.2015

Dr. Kathy D. Miller, MD Indiana University Melvin and Bren Simon Cancer CenterMedicalResearch.com Interview with: Dr. Kathy D. Miller, MD Indiana University Melvin and Bren Simon Cancer Center Medical Research: What is the background for this study? What are the main findings? Dr. Miller: Previous studies had found a small but real benefit with the addition of chemotherapy to anti-estrogen treatment in patients with hormone sensitive disease. The challenge for patients and clinicians has always been that the benefit of chemotherapy is quite small and the toxicity can be substantial. The Oncotype Dx recurrence score assay was developed to identify patients who could safely be treated with anti-estrogen therapy alone (and conversely those who truly need and would derive a much larger benefit from chemotherapy). When the Oncotype Dx RS was applied to samples stored from a previous randomized trial, patients with low risk scores didn't seem to benefit from chemotherapy. While those initial results had some impact on treatment, many were concerned about eliminating chemotherapy on the basis of one small retrospective trial. The overall trial enrolled 10,253 women. 1626 (15.9%) had a Recurrence Score of 0-10 and were assigned to receive antiestrogen therapy alone without chemotherapy. After five years 99.3% (98.7, 99.6%) for were free of distant relapse (that is to say, 99.3% of women had NOT had recurrence of breast cancer at distant sites in the body). Overall survival was 98%. (more…)