Alzheimer's - Dementia, Author Interviews, Genetic Research / 25.07.2018

MedicalResearch.com Interview with: Gregory Carter, PhD Associate Professor at The Jackson Laboratory MedicalResearch.com: What is the background for this study? What are the main findings? Response: Late-onset Alzheimer’s disease (LOAD) is the most common form of the disease and the major cause of dementia in the aging population. To date, the complex genetic architecture of LOAD has hampered both our ability to predict disease outcome and to establish research models that effectively replicate human disease pathology. Therefore, most basic research into Alzheimer’s disease has focused on early-onset forms caused by mutations in specific genes, which has provided key biological insights but to date has not translated to effective disease preventatives or cures. Our study analyzes both common and rare human genetic variants to identify those significantly associated with .late-onset Alzheimer’s disease, beginning with a large data set from the Alzheimer’s Disease Sequencing Project. We also analyzed RNA sequencing data from post-mortem human and mouse model samples to prioritize candidate genes. We found a new common coding variant significantly associated with disease, in addition to those in genes previously associated with late-onset Alzheimer’s disease. We also found five candidate genes conferring a significant rare variant burden.  (more…)
Author Interviews, Brigham & Women's - Harvard, Genetic Research, Microbiome / 24.07.2018

MedicalResearch.com Interview with: A. Sloan Devlin, PhD Assistant Professor Department of Biological Chemistry and Molecular Pharmacology Harvard Medical School MedicalResearch.com: What is the background for this study? Response: It is known that the microbiome, the collection of bacteria that live in and on our bodies, influences the development of metabolic diseases including diabetes and obesity. The ways in which the microbiome affects host metabolism, however, are poorly understood. One reason for this lack of understanding is because the gastrointestinal tract contains hundreds of species of bacteria producing many different kinds of metabolites. Untangling the effects of these bacteria and the molecules they make is a significant challenge. In this study, we decided to concentrate on a group of metabolites found in the human gut called bile acids. When we eat a meal, these compounds are released into the gastrointestinal tract where they act as detergents that aid in digestion. Once these molecules reach the lower gastrointestinal tract, the gut bacteria residing there chemically modify these compounds, producing a pool of over 50 different bile acids total. Imbalances in this bile acid pool are thought to influence the progression of diet-induced obesity. However, it is unclear which specific bile acids are responsible for either beneficial or detrimental effects on host metabolism. We set out to address this question by first identifying a selective type of bacterial enzyme called a bile salt hydrolase, then by genetically deleting this enzyme from a common gut bacterium and investigating how this change affected host metabolism. (more…)
Author Interviews, Biomarkers, Cancer Research, Genetic Research, Prostate Cancer / 23.07.2018

MedicalResearch.com Interview with: Gong-Hong Wei, PhD Professor, Academy Research Fellow Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu University of Oulu, Finland MedicalResearch.com: What is the background for this study? What are the main findings? Response: Prostate cancer is the second most common cancer and the fifth leading cause of cancer-related death in men, with more than 1,100,000 new cases diagnosed and 300,000 deaths yearly around the globe. Among the risk factors for prostate cancer development, the genetic heritability of prostate cancer has been reported near 60%. Over the past decade, genome-wide association studies have identified more than 150 independent single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, we know very little mechanisms accounting for these associations. SNP rs11672691 at the chromosome 19q13 locus has been found not only associated with prostate cancer risk but also aggressiveness, a form of prostate cancer often with worse prognosis and eventually progression to incurable stage. However, how this genomic variant accounts for prostate cancer severity remains totally unknown. Here we found the association of rs11672691 with additional clinical features of aggressive prostate cancer in an independent cohort of patients with prostate cancer, and discovered a rs11672691-mediated gene regulatory network including several novel genes, HOXA2, CEACAM21 and PCAT19, likely causing prostate cancer progression to incurable stage. In particular, the risk G (guanine) allele of rs11672691 was associated with higher RNA levels of PCAT19 and CEACAM21, and poor prognosis in prostate cancer patients. Rs11672691 G allele enhances chromatin binding of HOXA2 to regulate the expression of CEACAM21 and PCAT19. Using the CRISPR-Cas9 genome editing method, we revealed that rs11672691 genotype directly influence HOXA2 in regulating PCAT19 and CEACAM21 expression, and prostate cancer cellular phenotype. (more…)
Author Interviews, Breast Cancer, Cancer Research, Genetic Research, Nature / 23.07.2018

MedicalResearch.com Interview with: Luca Magnani, Ph.D CRUK Fellow/Senior Research Fellow Department of Surgery and Cancer Imperial Centre for Translational and Experimental Medicine Room 140 1st floor ICTEM building Imperial College Hammersmith London, UK MedicalResearch.com: What is the background for this study? Would you briefly explain what is meant by the Yin Yang1 molecule? Response: This study was designed to investigate the evidence of non-genetic mechanisms that could contribute to breast cancer biology. Specifically, we developed a map of regulatory regions from luminal breast cancer patients. Regulatory regions are pieces of DNA that are not transcribed into protein-coding genes but they provide information about where and how much each gene should be activated. It is worth highlighting that cancer is not only the consequence of gene mutations but also the result of the wrong genes expressed at the wrong time.  To catalogue regulatory regions we looked for specific modifications that are strongly associated with their activity (epigenetic modifications). Doing so we developed the first extensive catalogue  of non-coding DNA regions that might play an essential role in regulating how breast cancer cell behaves. Regulatory regions do their job by interacting with specific molecules called transcription factors. These molecules can read the information stored in these regulatory regions and contribute to regulate gene expression. Yin Yang 1 is one of such molecules and was previously thought as a ambiguous player capable of activating or repressing gene activity.   (more…)
Author Interviews, Genetic Research, Weight Research / 21.07.2018

MedicalResearch.com Interview with: “In-N-Out meal #1” by Chris Makarsky is licensed under CC BY 2.0Dr. Christina Holzapfel PhD Junior Research Group Leader at Institute for Nutritional Medicine Technical University of Munich MedicalResearch.com: What is the background for this study? What are the main findings? Response: A lot of articles about genetic factors and nutritional intake have been published in the last years. Findings are inconsistent and it is not clear, whether genetic variants, especially associated with body mass index, are associated with nutritional intake. Therefore we performed a systematic literature search in order to get an overview about the association between single nucleotide polymorphisms and total energy, carbohydrate and fat intakes. We identified about specific search terms and their combinations more than 10,000 articles. Of these, 39 articles were identified for a relationship between genetic factors and total energy, carbohydrate, or fat consumption. In all studies, we most frequently encountered the fat mass and obesity (FTO) associated gene as well as the melanocortin 4 receptor gene (MC4R). There are indications of a relationship between these two genes and total energy intake. However, the evaluation of the studies did not provide a uniform picture. There is only limited evidence for the relationship between the FTO gene and low energy intake as well as between the MC4R gene and increased energy intake. (more…)
Author Interviews, Biomarkers, Brain Cancer - Brain Tumors, Cancer Research, Genetic Research / 21.07.2018

MedicalResearch.com Interview with: Arnab Chakravarti MD Professor and Chair of Radiation Oncology Arthur G. James Cancer Hospital and Richard J. Solove Research Institute The Ohio State University Comprehensive Cancer Center MedicalResearch.com: What is the background for this study?   Response: Historically, the treatment for grade two gliomas has been a black box without really a standard-of-care therapy. In the past, it was really dealer’s choice, where it was based upon physician and patient preference. Either radiation alone, radiation plus chemotherapy, or chemotherapy alone, there wasn't really any data to guide therapeutic decision-making. Then about three years ago the landmark study RTOG 9802 was published, which demonstrated a survival benefit with the addition of chemotherapy to radiation versus radiation alone. That became the standard of care for the treatment of grade two gliomas. One of the tricky issues with regards to these tumors is that there's a wide range of outcomes. There are patients that succumb to disease within months, others that live decades. It's very important to personalize care for the individual patient and that's why biomarkers, prognostic and predictive biomarkers are so important. The 9802 study showed us for the general population of patients that the addition of chemotherapy to radiation improved outcomes versus radiation alone. The patient population that was selected for our study were the high-risk low-grade glioma patients. Patients who are generally over the age of 40, tumor sizes that exceeded 6 cm in terms of maximum dimension, tumors that invaded the corpus callosum, astrocytic histology of patients with neurological symptoms. These are typically the patients that were included in the study. Really the main objective of this study was to determine the efficacy of treatment compared to historical controls. (more…)
Addiction, Author Interviews, Cocaine, Genetic Research / 17.07.2018

MedicalResearch.com Interview with: “Cocaine concealed in washing powder” by The National Crime Agency is licensed under CC BY 2.0 MedicalResearch.com: What is the background for this study? What are the main findings?  Response: Drug addiction is a chronically relapsing neuropsychiatric disease that affects 15.5 million people in Europe at a cost of 65.7 billion euros per year. All addictive drugs have in common to cause an artificial increase in the release of a neurotransmitter called dopamine, a very basic effect that can be found in all studied animal species from the fly to the man. The release of dopamine takes place in a region of the brain called the ventral striatum, or Nucleus Accumbens (NAc), which is directly involved in reward and reinforcement processes. An excess of dopamine release by the dopaminergic neurons projecting to the NAc from the Ventral Tegmental Area (VTA) triggers long-term changes in the brain, which can lead to addiction. Cocaine is a prototypical addictive drug, since it is heavely abused in Western societies and extensively studied in animal models as well as humans. We discovered that mice lacking the Maged1 gene showed a marked decrease in cocaine-elicited release of dopamine in the NAc and were entirely unresponsive to cocaine at behavioral level. In fact, they did not show any behavioral reaction normally observed after cocaine treatment, such as cocaine-elicited hyperlocomotion, sensitization (an increased effect of the drug following repeated administrations) or addictive behaviors, such as increased preference for places where the animal expects to obtain a cocaine reward or cocaine self-administration. In a subsequent set of experiments, the researchers tried to identify what brain regions are responsible for Maged1 influence on cocaine effects and found that Maged1 expression is specifically required in the prefrontal cortex, and not in the neurons producing dopamine in the VTA, for the development of cocaine sensitization and dopamine release.  (more…)
Aging, Author Interviews, Genetic Research / 09.07.2018

MedicalResearch.com Interview with: “siblings” by Katina Rogers is licensed under CC BY 2.0Stacy L. Andersen, PhD Assistant Professor of Medicine Project Manager New England Centenarian Study Long Life Family Study Boston University School of Medicine Boston Medical Center Boston, MA 02118 MedicalResearch.com: What is the background for this study? Response: Exceptional longevity appears to run in families. Previous studies have found that people who have siblings who live into their 90s or who reach 100 years of age have a greater chance themselves of living longer than the general population. Yet it is supercentenarians, those who reach the age of 110 years, who represent the true extreme of the human lifespan.  We wanted to determine whether the parents and siblings of supercentenarians were more likely to reach very old ages than family members of younger centenarians. We collected family tree information for 29 participants of the New England Centenarian Study aged 110-119 years. Proof of age documents and familial reconstruction methods were used to validate ages and dates of birth and death of the supercentenarian as well as his or her parents and siblings. Mean age at death was compared to birth year and sex-specific US and Swedish cohort life table estimates conditional on survival to age 20 for siblings to omit deaths due to nonheritable factors such as infectious disease or accidents and survival to age 50 (the approximate age at which women are no longer able to reproduce) for parents.  (more…)
Alcohol, Author Interviews, Endocrinology, Genetic Research / 28.06.2018

MedicalResearch.com Interview with: Toni Pak, Ph.D. Professor and Department Chair Department of Cell and Molecular Physiology Loyola University Chicago Maywood, Ill  MedicalResearch.com: What is the background for this study? Response: We have known for many years that drinking alcohol during pregnancy can lead to developmental delays and birth defects in offspring. However, our data demonstrate that drinking large quantities of alcohol in a “binge” fashion before pregnancy can also impact future offspring and importantly, this is true for drinking behaviors of both parents, not just the mother. Our previous data support the idea that alcohol is affecting the parental sperm and eggs to induce these modifications in the offspring, but this most recent work shows the extent of those effects on social behavior, pubertal maturation, and stress hormones as the offspring grow to adulthood. This means that the risky behaviors of young people, such as the extremely popular practice of binge drinking, have potentially far-reaching consequences for generations to come. (more…)
Author Interviews, Cancer Research, Genetic Research, Nature, Prostate Cancer / 13.06.2018

MedicalResearch.com Interview with: Fredrick R. Schumacher, PhD, MPH. Associate Professor, Department of Population & Quantitative Health Sciences Case Western Reserve University Cleveland MedicalResearch.com: What is the background for this study? What are the main findings?  Response: Our study examines the genetic underpinnings of prostate cancer initiation using technology to test variants across the genome. Our study focused on men of European ancestry and included over 80,000 men with prostate cancer and 60,000 men without disease. We discovered 63 novel genetic variants associated with prostate cancer risk, which increases our knowledge of prostate cancer genetic risk factors by more than 60%. A genetic risk score created from the combination of 163 new and known prostate cancer risk variants revealed men with the highest genetic risk score are nearly seven times more likely to develop disease compared to the average man. Additionally, men with the lowest genetic risk score have a 85% risk reduction of developing prostate cancer compared to the average. Lastly, these new discoveries uncover several biological mechanisms involved in the initiation of prostate cancer. (more…)
Author Interviews, Genetic Research, Schizophrenia, UCSD / 12.06.2018

MedicalResearch.com Interview with: Marcelo Pablo Coba PhD Assistant Professor of Psychiatry Zilkha Neurogenetic Institute Keck School of Medicine of USC MedicalResearch.com: What is the background for this study? What are the main findings? Response: Psychiatric diseases such as schizophrenia (SCZ) are complex brain disorders where a multitude or risk factors have been implicated in contributing to the disease, with a low number of genes that have been strongly implicated in a very low number of cases. One of these genes is Disrupted in schizophrenia 1 (DISC1), which was first described in 2000 as a balanced translocation that segregates with schizophrenia and related psychiatric disorders in a large Scottish family. Because DISC1 does not have an identified protein function such as enzymatic, channel, transporter, etc… the field moved to try to understand what proteins are associated (physically connected) to DISC1 and to try to explain DISC1 function through the function of its protein interactors. This means that if DISC1 binds proteins X, Y and Z, then mutations in the DISC1 gene should affect the functions of   these proteins. Therefore, there has been much effort in trying to identify DISC1 protein interactors. However this task has not been straightforward. (more…)
Author Interviews, Genetic Research / 09.06.2018

MedicalResearch.com Interview with: “The human Brain” by Kristian Mollenborg is licensed under CC BY 2.0David Haussler PhD Investigator, Howard Hughes Medical Institute Distinguished Professor, Biomolecular Engineering Scientific Director, UC Santa Cruz Genomics Institute Scientific Co-Director, California Institute for Quantitative Biosciences  and Sofie Salama, PhD Research Scientist in BIomolecular Engineering Howard Hughes Medical Institute Senior Scientist MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Haussler:  Researchers specializing in this area are interested understanding which evolutionary changes in our genome underlie human-specific brain features including our large (3X greater than chimpanzee) brain. It has been my personal dream to peer into human evolution at the level of individual genes and gene functions.  (more…)
Author Interviews, Dermatology, Genetic Research / 22.05.2018

MedicalResearch.com Interview with: http://www.proqr.com/team-and-boards/Daniel de Boer Founding Chief Executive Officer ProQR MedicalResearch.com: What is the background for this study? Would you briefly explain what is meant by dystrophic epidermolysis bullosa? Response: Dystrophic epidermolysis bullosa (DEB) is caused by a mutation in the COL7A1 gene which is responsible for the formation of a protein called type VII collagen (C7). This protein helps bind the inner and outer layers of the skin together. Mutations in one part of COL7A1 gene, exon 73, are the most common cause of DEB resulting in a non-functional C7 protein. ProQR's QR-313 is designed to skip exon 73 of the COL7A1 gene, leading to a shortened C7 protein called C7Δ73. The current studies are intended to determine whether C7Δ73 functions the same as normal C7 protein. This mechanism can hopefully restore normal skin function for DEB patients. DEB is a rare genetic skin disease characterized by easy blistering of the skin, poorly healing wounds and skin infections. DEB is present at birth and in severe cases leads to skin cancer, which can significantly reduce a patient’s lifespan. There are currently no treatments for DEB that target the underlying cause of the disease. The current standard of care consists of expensive time-consuming wound care, antibiotics to prevent infection and pain medications. As a result, this disease presents a huge burden to the patients themselves, as well as people who help with daily care. (more…)
Author Interviews, Genetic Research, Pediatrics, Weight Research / 22.05.2018

MedicalResearch.com Interview with: “Great Grandmother” by David Amsler is licensed under CC BY 2.0Rebecca Somerville MB BCh BAO, BMedSci, MRCPI, MPH, PhD School of Public Health, Physiotherapy and Sports Science University College Dublin Dublin, Ireland  MedicalResearch.com: What is the background for this study? What are the main findings?  Response: Rates of obesity in the Western world have increased dramatically over recent decades. The negative health consequences of obesity are well known and significant amounts of research have been conducted into the causes and possible solutions. While it is clear that there have been massive changes in diet and physical activity at a societal level that are primarily responsible for this 'obesity epidemic', it is less clear the extent to which obesity, once established, or risk factors for same, can be perpetuated down generations. Family studies lend opportunity to explore these questions, however there are few world wide which incorporate 3 generations. We therefore sought to examine patterns of central adiposity, as measured by waist circumference, between grandparents and their grandchildren, separately in maternal and paternal lines. We were able to utilize prospectively collected data from the Lifeways Cross-Generation Cohort Study. This is a longitudinal birth cohort, established in Ireland in 2001, involving up to 7 members of the same family (mother, father, child and 4 grandparents). In the 589 families where a child had a waist circumference measurement we found that, at the age of both 5 and 9, there was a direct relationship between the waist circumference of the maternal grandmother and her grandchild (both male and female). This remained after adjustment for a wide range of confounding variables including mother's waist circumference. There was no relationship seen with any of the other grandparents. (more…)
Author Interviews, Exercise - Fitness, Genetic Research, Heart Disease / 19.05.2018

MedicalResearch.com Interview with: Prof. Patricia Munroe PhD Professor of Molecular Medicine William Harvey Research Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London MedicalResearch.com: What is the background for this study? Response: Over the years, it has become increasingly evident that impaired capacity to increase heart rate during exercise and reduce heart rate following exercise are important predictors of all-cause and cardiovascular mortality. A person's capability to regulate their heart rate is the result of complex interactions of biological systems, including the autonomic nervous and hormonal systems. Prior work has demonstrated that genetic factors significantly contribute to variations in resting heart rate among different individuals, but less was known about the genetic factors modulating the response of heart rate to exercise and recovery. (more…)
AHA Journals, Author Interviews, Genetic Research, Heart Disease, Lipids, Vanderbilt / 18.05.2018

MedicalResearch.com Interview with: Wei-Qi Wei, MD, PhD Assistant Professor Department of Biomedical Informatics Vanderbilt University Nashville, TN 37203 MedicalResearch.com: What is the background for this study? What are the main findings? Response: The study was motived by the clinical observation that some patients develop coronary heart disease events despite taking statins, one of our most effective drugs to reduce cardiovascular risk. We collected data within the eMERGE network of people taking statins and monitored them for development of coronary heart disease events over time.  We  conducted a genome-wide association study of those with events compared to those without events. Our results showed that single nucleotide polymorphisms (SNPs) on the LPA gene were associated with a significantly increased risk of coronary heart disease events. Individuals with the variant were 50% more likely to have an event. More importantly, even among patients who achieved ideal on-treatment LDL cholesterol levels (<70 mg/dL), the association remained statistically significant. We then did a phenome-wide association study to see if other diseases or conditions were associated with these LPAvariants. The major associated conditions were all cardiovascular. This sort of study can highlight potential other indications for a drug targeting this pathway and suggest potential adverse events that might be experienced from targeting this pathway. Clearly, more and larger studies will be needed to truly understand the potential risks and benefits of a future drug targeting this pathway.  (more…)
Author Interviews, Genetic Research, JAMA, Schizophrenia / 17.05.2018

MedicalResearch.com Interview with: Tobias Kaufmann PhD Norwegian Centre for Mental Disorders Research (NORMENT), KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine University of Oslo, Oslo, Norway MedicalResearch.com: What is the background for this study? What are the main findings? Response: Over the past years, a lot of work has pointed toward impaired brain networks in schizophrenia. With this work we assessed brain network stability across different loads of a cognitive task using functional magnetic resonance imaging of the brain. Based on our earlier work on adolescents with pre-clinical signs of mental illness who showed decreased stability of networks across different tasks and conditions, we hypothesized that brain networks in adults with schizophrenia show similar properties of decreased stability. Our results confirmed this hypothesis. Stability was reduced in several large-scale brain networks across the sampled age range from early adulthood to the sixties. Further, network stability was associated with polygenic risk for schizophrenia as well as cognitive task performance. (more…)
Author Interviews, Genetic Research, JAMA, UCSF / 12.05.2018

MedicalResearch.com Interview with: Allison W. Kurian, M.D., M.Sc. Associate Professor of Medicine (Oncology) and of Health Research and Policy Director, Women’s Clinical Cancer Genetics Program Stanford University School of Medicine Stanford, CA 94305-5405  MedicalResearch.com: What is the background for this study? What are the main findings? Response: Changes in genetic sequencing technology and regulation have allowed much cheaper testing of many more genes in recent years. We investigated how these changes have affected hereditary cancer risk evaluation in women newly diagnosed with breast cancer. The main findings are that more comprehensive multiple-gene sequencing tests have rapidly replaced more limited tests of two genes (BRCA1 and BRCA2) only. This has helped patients by doubling the chance of finding an important gene mutation that can change their treatment options. However, there are important gaps in how this new, more comprehensive sequencing is used: more testing delays and more uncertain results, particularly among racial/ethnic minority women.  (more…)
Author Interviews, BMJ, Genetic Research, Pediatrics / 10.05.2018

MedicalResearch.com Interview with: “Newborn” by Brad Carroll is licensed under CC BY 2.0Dr Sian Taylor-Phillips MPhys, PhD Associate Professor Screening and Test Evaluation / NIHR Career Development Fellow Division of Health Sciences Warwick Medical School University of Warwick Coventry MedicalResearch.com: What is the background for this study? What are the main findings? Response: In newborn blood spot screening a small amount of blood is taken from newborn babies heels, and this is tested for a range of rare diseases. The idea is to detect each disease earlier when it is more treatable. However, it would be better not to test for some diseases, for example if the test is inaccurate so worries parents that their baby may have a serious illness when they do not. Some countries test for as few as 5 diseases and others as many as 50. In this study we investigated how different countries choose which diseases to test for. We found that many national recommendations on whether to screen newborn babies for rare diseases do not assess the evidence on the key benefits and harms of screening. Evidence about the accuracy of the test was not considered in 42% of recommendations, evidence about whether early detection at screening has health benefits was not consulted in 30% of recommendations, and evidence around the potential harm of overdiagnosis where babies have variants of the disease that would never have caused any symptoms or ill effects was not considered in 76% of recommendations. We also found through meta-analysis that when a systematic review was used to bring together the evidence then countries were less likely to recommend screening for the disease. (more…)
Author Interviews, Genetic Research, Weight Research / 09.05.2018

MedicalResearch.com Interview with: “Mmm...hamburgers” by jeffreyw is licensed under CC BY 2.0Dr. Peter Kühnen Institute for Experimental Pediatric Endocrinology Charité Universitätsmedizin Berlin Berlin Germany  MedicalResearch.com: What is the background for this study? What are the main findings?  Response: We are focusing our interest on rare monogenic forms of obesity. The hormones leptin and MSH are playing a pivotal role for the regulation of satiety and body weight. Mutations within this pathway, e.g. in the leptin receptor gene, are leading to severe hyperphagia and early onset obesity.  Although tremendous effort it is extremely difficult for the affected patients to stabilize their body weight for a longer period of time. For this reason it has been analyzed within this investigated initiated trial whether patients with a leptin receptor mutation benefit from a treatment with the MC4R agonist setmelanotide. The treatment led to a reduction of the initially increased hunger feeling and to a reduction of body weight. Additionally, we identified molecular evidences that a specific signaling cascade of the MSH receptor (MC4R) is of importance for the regulation of body weight. (more…)
AACR, Author Interviews, Genetic Research / 18.04.2018

MedicalResearch.com Interview with: Ed Liu, M.D President and CEO The Jackson Laboratory (JAX) MedicalResearch.com: What is the background for this study? What are the main findings? Response: A few years ago we and others identified a complex genomic instability profile commonly found in the genomes of breast, ovarian and endometrial carcinomas, which is characterized by hundreds of isolated head-to-tail duplications of DNA segments, called tandem duplications. We refer to this configuration as the tandem duplicator phenotype, or TDP. In this study, we perform a meta-analysis of over 2,700 cancer genomes from over 30 different tumor types and provide a detailed description of six different types of TDP, distinguished by the presence of tandem duplications of different sizes. Collectively, these profiles are found in ~50% of breast, ovarian and endometrial carcinomas as well as 10-30% of adrenocortical, esophageal, stomach and lung adeno-carcinomas. We show that distinct genetic abnormalities associate with the distinct TDPs, clearly suggesting that distinct molecular mechanisms are driving TDP formation. In particular, we provide strong evidence of a casual relationship between joint abrogation of the BRCA1 and TP53 tumor suppressor genes and the emergence of a short-span (~11 Kb) TDP profile. We also observe a significant association between hyper-activation of the CCNE1 pathway and TDP with medium-span (~230 Kb) tandem duplications, and between mutation of the CDK12 gene and medium- and large-span TDP (coexisting 230 Kb and 1.7 Kb tandem duplications). Importantly, we find that different forms of TDP result in the perturbation of alternative sets of cancer genes, with short-span TDP profiles leading to the loss of tumor suppressor genes via double transections, and larger-span TDP profiles resulting in the duplication (i.e. copy number gain) of oncogenes and gene regulatory elements, such as super-enhancers and disease-associated SNPs.  (more…)
Author Interviews, Genetic Research, Heart Disease, JAMA / 06.04.2018

MedicalResearch.com Interview with: Stella Aslibekyan, PhD Associate Professor PhD Program Director Department of Epidemiology University of Alabama at Birmingham MedicalResearch.com: What is the background for this study? What are the main findings? Response: When the human genome was sequenced in 2003, there were somewhat unrestrained expectations of unraveling all etiologic mysteries and discovering breakthrough treatments. Needless to say, that did not happen, in part because individual genetic variants can only account for a small fraction of trait variability. Since then, epigenetics-- the study of mitotically heritable changes in gene expression-- has emerged as another promising avenue for understanding disease risk. The best studied epigenetic process in humans is DNA methylation, and earlier studies (including some from our group) have shown interesting associations between changes in methylation in specific genomic regions and cardiovascular disease traits, e.g. plasma cholesterol levels. In this project, we have combined DNA methylation data on thousands of individuals from multiple international cohorts and interrogated epigenetic contributions to circulating tumor necrosis factor alpha (TNFa), a marker of systemic inflammation. We identified and replicated several epigenomic markers of TNFa, linked them to variation in gene expression, and showed that these methylation changes (which were located in interferon pathway genes) were predictive of coronary heart disease later in life. Interestingly, the variants we discovered were not sequence-dependent (in other words, they were not associated with any genetic mutations), highlighting the role of the environment. (more…)
Author Interviews, Genetic Research, Ophthalmology / 05.04.2018

MedicalResearch.com Interview with: Wen-Tao Deng, Ph.D. Department of Ophthalmology, College of Medicine| University of Florida, Gainesville, FL MedicalResearch.com: What is the background for this study? What are the main findings? Response: Blue cone monochromay (BCM) is a devastating vision disorder characterized by loss function of both L- and M-cones due to mutations in the L- and M-opin gene cluster on the X chromosome. BCM patients display severely reduced visual acuity, loss of color-vision, myopia, nystagmus, and minimally detectable cone-mediated electroretinogram. In our studies, we showed that an M-opsin knockout mouse model resembles human BCM, and expression of either human M- or L-opsin individually or combined through adeno-associated viral vector promotes regrowth of cone outer segments and rescues M-cone function in the treated M-opsin dorsal retin (more…)
Author Interviews, Colon Cancer, Genetic Research, JAMA / 03.04.2018

MedicalResearch.com Interview with: Heather Hampel, MS, LGC Associate Director, Division of Human Genetics Associate Director, Biospecimen Research Professor, Internal Medicine Licensed Genetic Counselor The Ohio State University Comprehensive Cancer Center Columbus, OH  4322 MedicalResearch.com:  What is the background for this study?  What are the main findings? Response: The background is that we had recently shown that some colorectal cancer patients who underwent traditional screening for Lynch syndrome were eventually found to have double somatic (two acquired) mutations in the MMR genes and they did not have Lynch syndrome at all. This was discovered after their tumor had already had MSI and/or IHC screening test, followed by MLH1 methylation and/or BRAF testing, followed by germline DNA testing on a blood sample from the patient for MMR gene mutations, then finally by sequencing their tumor. This gave us the idea to reverse the sequence and start with tumor sequencing since it might streamline testing, save time, and prevent several other tests. In addition, we knew that all stage IV colorectal cancer are already supposed to have tumor sequencing of the KRAS, NRAS, and BRAF genes and MSI testing for treatment purposes. Our hypothesis was that an upfront tumor sequencing test could replace all these separate tests with similar sensitivity and specificity. (more…)
Author Interviews, Genetic Research, Nature, OBGYNE, UCLA / 22.03.2018

MedicalResearch.com Interview with: Marlena Fejzo, PhD Aassociate researche David Geffen School of Medicine UCLA.  MedicalResearch.com: What is the background for this study? Response: Most women experience some nausea and vomiting of pregnancy, and the worst 2% are diagnosed with Hyperemesis Gravidarum which is associated with poor maternal and fetal outcomes. I had HG in 2 pregnancies. In my second pregnancy my HG was so severe that I could not move without vomiting and did not keep any food or water down for 10 weeks. I was put on a feeding tube, but ultimately lost the baby in the second trimester. I am a medical scientist by training so I looked into what was known about HG. At the time, very little was known, so I decided to study it. I partnered with the Hyperemesis Education and Research Foundation (HER) and we did a survey on family history of .Hyperemesis Gravidarum that provided evidence to support a role for genes. I collected saliva samples from HG patients and their unaffected acquaintances to do a DNA study. Then I partnered with the personal genetics company, 23andMe to do a genome scan and validation study, which identified 2 genes, GDF15 and IGFBP7, linked to HG. (more…)
Author Interviews, Biomarkers, Breast Cancer, Cancer Research, Genetic Research / 26.02.2018

MedicalResearch.com Interview with: Maureen E. Murphy, Ph.D. Program Leader and Professor Molecular and Cellular Oncogenesis and Subhasree Basu PhD Postdoctoral researcher The Wistar Institute Philadelphia, PA 19104 MedicalResearch.com: What is the background for this study? What are the main findings? Response: Unlike most other genes that are intimately involved in the cause of cancer, the p53 gene displays considerable genetic variation; in other words, p53 is unusual among cancer genes in that the amino acids in p53 protein can frequently differ amongst different populations and ethnic groups. Additionally, unlike most other tumor suppressor genes, when p53 is mutated in a tumor, as it is in 50% of human cancers, that mutant protein now has a positive function in cancer progression, changing tumor metabolism and promoting tumor metastasis. In this study, the authors analyze for the first time the impact of a common genetic variant in p53 (single nucleotide polymorphism, or SNP) in the ability of mutant p53 to promote tumor metabolism and metastasis, and they find significant differences.  (more…)
Author Interviews, Breast Cancer, Genetic Research / 19.02.2018

MedicalResearch.com Interview with: Amanda Toland, PhD, Cancer biology and genetics researcher of The Ohio State University Comprehensive Cancer Center -- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute MedicalResearch.com: What is the background for this study? What are the main findings? Response: The Breast Information Core (or BIC) is a database that catalogs BRCA1 and BRCA2 sequenced variants.  The BIC is hosted by the National Human Genome Research Institute at NIH and has a steering committee that oversees the BIC and has members from Europe, the middle East, Australia and the US.  In BIC SC discussions, we learned that there are differences in how BRCA1/2 clinical is testing between countries. To characterize this variation, we performed an international survey of 86 genetic testing labs from around the world. Our main findings are that there were many variations between testing laboratories.  These include: technologies differed for finding “large” genetic sequence variants, what parts of the genes were assessed, how genetic variants were classified as disease associated or not being associated with diseases, if genetic sequencing information was shared in public databases and testing volume. (more…)
Author Interviews, Dengue, Genetic Research, PLoS / 16.02.2018

MedicalResearch.com Interview with: Luisa Pereira PhD Institute for Research and Innovation in Health University of Porto  MedicalResearch.com: What is the background for this study? What are the main findings? Response: By using admixture mapping along the genome in Thai cohorts, we were able to identify new candidate genes conferring protection/susceptibility to dengue fever. A very interesting result was that the set of genes differed with the dengue phenotype: genes coding proteins that may link to the virus, conditioning its entrance in the host cells and mobility therein were associated with the less severe phenotype; genes related with blood vessels permeability were associated with the dengue shock syndrome.  (more…)