MedicalResearch.com Interview with:
Stephen F. Kingsmore MB ChB BAO DSc FRCPath
Dee Lyons/Missouri Endowed Chair in Genomic Medicine,
Children’s Mercy - Kansas City
Medical Research: What is the background for this study?
Response: The background to this study is that genetic diseases are the leading cause of death in infants and, especially, in infants in neonatal intensive care units. Making a molecular (etiologic) diagnosis of the specific genetic disease is critical for optimal care and decision making for acutely ill infants who are likely to have such diseases. However there are over 5000 known genetic diseases and their presentations overlap considerably in infants. Until now it has not been possible to make timely diagnoses in these infants.
Medical Research: What are the main findings?Response: Rapid whole genome sequencing is a new way of making a genetic disease diagnosis in acutely ill newborns in neonatal intensive care units. It appears to be effective for diagnosis.
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MedicalResearch.com Interview with:Nasim Mavaddat M.B.B.S. MPhil PhD PhD
Centre for Cancer Genetic Epidemiology
Department of Public Health and Primary Care
University of Cambridge, Cambridge, UK
MedicalResearch:What is the background for this study?
What are the main findings?Dr. Mavaddat: Recent large-scale genome wide association analyses have led to the discovery of genetic variation- called single nucleotide polymorphisms (SNPs) associated with breast cancer risk. Individually these variants confer risks that are too small to be useful for risk prediction. But when combined as a single score, called a polygenic risk score (PRS), this score may be used to stratify women according to their risk of developing breast cancer. This stratification could guide strategies for screening and prevention.
Our study was a large international collaboration involving 41 research groups from many different countries and included 33,673 breast cancer patients and 33,381 controls. We found that the genetic variants act more or less independently, and that the more risk variants a woman has the higher her risk of breast cancer. When women were ranked according to their PRS, women with scores in the top 1% had a threefold increased risk of breast cancer. This translates into an absolute risk of breast cancer of 29% by age 80. By contrast, women with the lowest 1% scores had a risk of 3.5%.
The PRS was effective in stratifying women with and without a family history of breast cancer, so that highest risk was for women with a family history and a high PRS. Finally, we showed that the PRS was better at predicting the risk of ER-positive breast cancer (potentially relevant to the application of risk stratification to chemoprevention for example, with tamoxifen, raloxifene or aromatase inhibitors).
There has been much debate as to whether genomic profiles are useful for individual risk prediction, especially in the context of the preventative strategies available at the present time. The estimates provided in this study will help inform these debates.
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MedicalResearch.com Interview with:
Pedram Gerami, M.D.
Associate Professor of Dermatology
Director, Melanoma Research
Northwestern Skin Cancer Institute
Northwestern University
MedicalResearch: What is the basis and background for performing this study?Dr. Gerami: Most of the existing literature shows that Sentinel Lymph Node Biopsy (SLNB) will identify 25 to 35 percent of patients who will ultimately die of metastatic melanoma. Hence while SLNB is reported to be the strongest predictor of outcome for melanoma, the vast majority of patients who ultimately die of metastatic melanoma have a negative Sentinel Lymph Node Biopsy result. Hence in this study we aimed to determine whether a GEP assay developed by Castle bioscience could be used independently or in conjunction with SLNB to better detect those patients who are at high risk for developing metastatic disease and dying from melanoma.
MedicalResearch: What are the findings of the study?Dr. Gerami: Our study, which examined the use of a Gene Expression Profile (GEP) assay developed by Castle Biosciences and Sentinel Lymph Node Biopsy alone and in combination in a multi-center cohort of 217 patients, demonstrated that the use of the GEP identified more than 80 percent of patients who develop melanoma
Combining the two methods showed that patients predicted to be high risk based on the GEP test alone had similar rates of disease progression whether they were SLNB positive or negative. Patients who were SLNB negative and predicted to be low risk using the GEP test had lower rates of disease progression than the SLNB negative group as a whole.
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MedicalResearch.com Interview with:
Melissa Wilson, MD, PhD
Assisstant Professor
Perlmutter Cancer Center
NYU Langone Medical Center
New York, NY
Medical Research: What is the background for this study? What are the main findings?
Dr. Wilson: Metastatic cutaneous melanoma is an extremely aggressive form of skin cancer. Traditionally, it has been characterized by clinicopathologic characteristics. More recently, melanoma tumors have also been stratified by common somatic mutations for which targeted therapies have been developed or are under investigation, including BRAF, NRAS and KIT. In addition to somatic mutations, aberrant intracellular signaling pathways and cell cycle disruption contribute to melanoma pathogenesis. Indeed, recent next generation sequencing studies have identified a number of new genes involved in melanomagenesis. A comprehensive evaluation and understanding of concurrent and mutually exclusive mutations in tumors has been lacking. Therefore, we developed a comprehensive custom targeted capture of 108 genes previously implicated in melanoma pathogenesis. We used the targeted panel to perform massively parallel sequencing on 94 well-established human melanoma cell lines, 67 patient-derived xenografts (PDX), and 5 cell lines made from PDX, all untreated.
Samples were clustered based on deleterious mutations. Eighty-three percent of samples had deleterious mutations in the MAPK signaling pathway (including BRAF, RAS) and NF1. Ten percent of samples had PI3K pathway mutations which were predominantly associated with BRAF mutations. TP53 was found to be mutated in 24% of the samples and were also associated with mutations in the MAPK pathway. Mutations in chromatin remodeling genes were mutually exclusive with each other, but were associated with BRAF and NRAS mutations. Of particular interest, five of the 10 NF1mutated samples harbored likely deleterious mutations in MAP3K5 or MAP3K9, suggesting the potential involvement of JNK signal transduction pathway in a cohort of samples.
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MedicalResearch.com Interview with:
Olivier Elemento, PhD
Associate Professor
Head, Laboratory of Cancer Systems Biology
Department of Physiology and Biophysics
Institute for Computational Biomedicine
Weill Cornell Medical...
MedicalResearch.com Interview with:
Dr. Agnieszka Witkiewicz MD
Associate Professor of Pathology
Harold C. Simmons Comprehensive Cancer Center
UT Southwestern
MedicalResearch: What is the background for this study? Dr. Witkiewicz: Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis, with a five year survival rate of approximately 6%. This poor outcome is related to multiple factors, including the relatively late stage of diagnosis, many patients presenting with unresectable disease, and therapy recalcitrance resulting in disease recurrence in spite of operable disease and systemic therapy. Thus far, insights into how to target the treatment of Pancreatic ductal adenocarcinoma have remained unclear in spite of prior sequencing efforts.
MedicalResearch: What are the main findings?Dr. Witkiewicz: The underlying critical finding of the study was that Pancreatic ductal adenocarcinoma is genetically diverse and that, in principle, this diversity could be exploited for the treatment of disease. Specifically, many cases harbored deregulation in pathways that are the target for drug development. For example, we identified cases that were driven by BRAF V600E and that were sensitive to the FDA approved drug Vemurafenib. Similarly, multiple cases harbored defects in DNA repair processes that impart sensitivity to select chemotherapeutic agents and PARP inhibitors. Common pathway deregulation was observed in reference to beta-catenin, notch, hedgehog, chromatin remodeling, and cell cycle regulatory pathways that are all targets for therapeutic intervention.
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MedicalResearch.com Interview with:
Nancy E. Thomas, MD, PhD
Department of Dermatology
University of North Carolina
MedicalResearch: What is the background for this study? Dr. Thomas: BRAF and NRAS mutations found in melanomas are important for tumor initiation and maintenance. There are drugs that target BRAF mutations or the pathway that are approved for BRAF-mutant metastatic melanoma and help improve survival. However, it remains unknown whether these mutations in primary melanoma are markers for melanomas with a worse prognosis.
MedicalResearch: What are the main findings?Dr. Thomas:
In a large international population-based study, we found that of primary melanomas, 30% harbor BRAF mutations, 13% have NRAS mutations and the other 57% do not have these mutations (wildtype).
In higher primary tumor stage melanomas, BRAF or NRAS mutations were associated with an approximately 3-fold increased rate of death from melanoma compared to wildtype melanoma adjusted for other prognostic factors.
Primary melanomas with NRAS mutations were less likely to have tumor infiltrating lymphocytes (TILs) in the tumor microenvironment. (more…)
MedicalResearch.com Interview with:Jeanne M. Meck, PhDFACMG
Director, Prenatal Diagnosis & Cytogenomic
GeneDx
Gaithersburg, MD 20877
Medical Research: What is the background for this study?
Dr. Meck: Non-invasive prenatal screening (NIPS) for fetal aneuploidy is a new test which requires only a blood sample from the pregnant mother to provide a risk estimate of whether or not her fetus has a chromosomal aneuploidy such as trisomy 21 (Down syndrome), trisomies 13 or 18, or a sex chromosome abnormality. This testing relies on the fact that circulating maternal blood contains cell free fetal DNA. Published studies have reported very high specificities and sensitivities. However, the more important question is what is the positive predictive value (PPV= #true positive results/#true positive + false positive results) since it answers the question of interest to physicians and patients: “Given an Non-invasive prenatal screening result that shows a high risk for a given fetal aneuploidy, what is the chance that the fetus is affected?” We attempted to answer this question by looking at the results of fetal chromosome analyses on chorionic villus samples (CVS) or amniotic fluid that were referred to our cytogenetics laboratories after Non-invasive prenatal screening in order to see if NIPS correctly predicted the fetal karyotype.
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MedicalResearch.com Interview with: Dr. Reshma Jagsi MD, DPhil
Associate Professor and Deputy Chair for Faculty and Financial Operations in the Department of Radiation Oncology at the University of Michigan Health System
Research Investigator at the Center for Bioethics and Social Sciences in Medicine
University of Michigan
Medical Research: What is the background for this study? What are the main findings?
Dr. Jagsi: We surveyed women diagnosed with breast cancer and found that many women were concerned about the genetic risk of developing other cancers themselves or of a loved one developing cancer. Overall, 35 percent of the women we studied expressed a strong desire for genetic testing, but 43 percent of those did not have a relevant discussion with a health care professional. In addition, minority patients with a strong desire for testing were less likely to discuss it with a professional, even though studies show that minority patients are not at lower risk for these mutations.
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MedicalResearch.com Interview with:
Thomas Perls, MD, MPH Professor
Boston University School of Medicine
Medical Research: What is the background for this study?
Dr. Perls: For years now, Gerontology scholars continue to state that 25% of what they interchangeably call aging, longevity, life expectancy and life span is genetic and 75% is due to the environment and health-related behaviors. This assertion is based on Scandinavian twins reared apart, but the oldest participants in those studies lived to their 70s and 80s. Part of the problem here is the lack of consistency in what people mean by the terms Aging, Life Span and Longevity.
In fact, the Seventh Day Adventists, who generally have a high prevalence of healthy behaviors (vegetarian, daily exercise, eat in moderation, abstain from tobacco and alcohol, and activities that help manage stress well) have an average live expectancy of approximately 88 years. Yet, 7th Day Adventists are ethnically and racially heterogeneous and thus it appears that those healthy behaviors explain the vast majority of the variation in how old these people live to be. This finding is consistent with the optimistic view of the twin studies, that much of living to one's 80's is in our hands. Living to only our 50s-70's is also in our hands (e.g. 75% behaviors) if we choose to smoke, eat red meat frequently, be obese, not exercise, be exposed to gun violence, have unsafe sex, do IV drugs, etc. So it is safe to say, in my opinion, that 75% of the variation in how old we live to be, is on average due to our behavior and exposure choices. The empowering and important point is that if we all lived like the Seventh Day Adventists, average life expectancy would increase almost 8 years and health costs would markedly decline because we would be getting to these older ages because we are healthier not because we are pouring more resources into more effectively treating diseases.
The New England Centenarian Study, which I direct, and a number of other studies of nonagenarians (people in their 90s) have demonstrated via direct genetic studies as well as studies of family trees where at least some family members get to these very old ages, that with older and older ages of survival beyond age ~95 years, variations in genetic profiles explain a greater and greater proportion of the variation in how old people live to be at these ages. So much so that I believe the findings to date are consistent with the roles of genes and environment being reversed for survival to age 106+ years, that is, 75% genetics and 25% environment/behaviors. This supposition is based upon several observations:
(1) as people reach the age of 105+ years, they become more and more alike in terms of what age-related diseases they get and when they get them. Consistent with Jim Fries; "Compression of Morbidity" hypothesis, people who survive to ages 110+ (called supercentenarians) and who therefore approximate the limit of human lifespan are on average disease and disability-free up until the last 5 or so years of their lives. This increasing homogeneity, especially compared to the increasing heterogeneity in the rates of aging and incidences of age-related diseases at younger percentiles or ages of survival, suggests underlying genetic similarities (similar genetic profiles) amongst groups of these supercentenarians; and
(2) the New England Centenarian Study previously discovered genetic signatures (made up of longevity-associated variations of about 130 genes) that were associated with surviving to age 106+ years with 80% accuracy, but with only 60% accuracy for accurately picking out people living to ~100 years. This increasing accuracy with older and older ages also suggests a stronger and stronger genetic influence upon survival to these rarest percentiles of survival.
With the above background, we set out in this study and subsequent paper, to
(1) assess sibling relative risk using the largest-ever collection of validated pedigrees of centenarians,
(2) to assess the risk of a sibling achieving the same age as their very old sibling (e.g. ages 95, 100, or 105+ years) relative to average people born around the same time, and
(3) to look at how when a person was born (eg before or after 1890) made a difference in these relative risks.
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MedicalResearch.com Interview with:
Jeff Coller, PhD Associate professor
Division of General Medical Science
Associate director, The Center for RNA Molecular Biology,
Case Western Reserve University School of Medicine
MedicalResearch: What is the background of this study?
Dr. Coller: There are a diverse number of half-lives for any individual messenger RNA (mRNA). The range of those half-lives is from seconds to hours. What the field has wanted to know for 30 years is how those rates are regulated, and there has been considerable anecdotal and real evidence that sequences in untranslated regions (UTRs) could regulate decay, but it doesn’t explain all of the half-lives that are observed for all messages. In addition, we have known mRNAs that are translated better are more stable than mRNAs that are translated poorly, so those pieces together led to the discovery.
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MedicalResearch.com Interview with:
Jay S. Kaufman, Ph.D
Canada Research Chair in Health Disparities
Department of Epidemiology, Biostatistics, and Occupational Health
McGill University
Montreal, Quebec Canada
Medical Research: What is the background for this study? What are the main findings?
Response: Published scientific articles speculate frequently about genetic predispositions in different racial groups as explanations for observed disease disparities. They infer this from the higher rates observed in racial minorities, even after adjusting for some social and behavioral measures. Taking the example of the racial disparity between blacks and whites in cardiovascular diseases (stroke, heart attack, heart failure, hypertension, etc), ours is the first published study to review all of the existing results from GWAS (genome-wide association studies) to see if they provide any support for this commonly stated position. To date, they do not. We performed an electronic literature search through the PubMed database to identify review articles and meta-analyses related to genetic risk factors for cardiovascular disease in samples that included populations of European and African ancestries. We focused our search on the 7-year period from January 1, 2007 to January 1, 2014, which corresponded to the rapid proliferation of large pooled GWAS activity. This search strategy yielded 197 review articles or meta-analyses. 68 of these articles contained relevant data, but very few reported significant associations in both racial groups, with just 3 variants meeting study-specific significance criteria. For most outcomes, there were too few estimates for quantitative summarization, but when summarization was possible, racial group did not contribute to heterogeneity. Most associations reported from genome-wide searches were small, difficult to replicate, and in no consistent direction that favored one racial group or another.
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MedicalResearch.com Interview with:
Matthew B. Yurgelun, MD
Instructor in Medicine
Harvard Medical School
Medical Research: What is the background for this study? What are the main findings?
Dr. Yurgelun: Germline mutations in the TP53 gene are linked to Li-Fraumeni syndrome, which is an inherited syndrome associated with a 73-100% lifetime risk of cancer. Classically, cancers linked to Li-Fraumeni syndrome include early-onset breast cancer, leukemias, soft tissue sarcomas, brain cancer, and adrenocortical cancer, although recent data have shown an increased risk of colorectal cancer as well. Our study’s primary aim was to determine the frequency of germline TP53 mutations in patients with early-onset colorectal cancer.
We studied 457 patients from the multinational Colon Cancer Family Registry who were diagnosed with colorectal cancer at age 40 or younger, and found that 1.3% carried a germline alteration in the TP53 gene. None of these individuals had personal or family histories of cancer that fulfilled clinical criteria for Li-Fraumeni syndrome. (more…)
MedicalResearch.com Interview with:
Prof. Moshe Szyf Ph.D.
James McGill Professor of Pharmacology and Therapeutics
McGill University
Medical Research: What is the background for this study? What are the main findings?Dr. Szyf: Humans exhibit a marked variation in traits both physical and behavioral and different susceptibilities for developing disease. What causes this inter-individual variation? The prevailing dogma has been that changes in the sequences of genes or heritable genetic differences are responsible for these differences. We tested here an alternative hypothesis that perhaps some of the reason for this natural variation in traits is not caused by differences in inherited genes but by “epigenetic” changes that alter the way genes work without changing the genes. The main difference between genetic and epigenetic changes is that epigenetic changes could be introduced by experience and exposure to environment. The experiences that can cause epigenetic changes include physical as well as social environments. Although we had known that epigenetic differences occur in humans and animals we didn’t have evidence that these changes are behind the natural variation in traits that is observed in humans and animals. Ants are an exciting biological paradigm that exhibits quantitative variations in size and therefore provided a unique opportunity to test this hypothesis.
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MedicalResearch.com Interview with:Dr. David M.G. Lewis, PhD
Assistant Professor Department of Psychology
Bilkent Üniversitesi Ankara, Turkey
Research Affiliate,
Individual Differences and Evolutionary Psychology Area
Department of Psychology
The University of Texas at Austin
MedicalResearch: What is the background for this study?
Dr. Lewis: My motivations to conduct this study were a combination of several things. Men would often mention to me the features that they found attractive in women. They would often mention the butt, but not the *size* of the butt...it was something else, but they couldn't seem to put their finger on exactly what...
I then began reading more deeply into the different muscular, ligamentous, skeletal, etc. structures that could influence the appearance of the buttocks. I moved beyond just buttock tissue and buttock size. What I began to discover is that while the size of the buttocks does indeed influence the buttocks' appearance, so too does other morphology that is not part of the buttocks themselves. These readings indicated that certain spinal structures can help women shift their center of mass back over the hips during pregnancy and reduce hip torque by roughly 700%. To the extent that women who possess these spinal structures would thereby be better able to carry a pregnancy (or multiple pregnancies) to term without suffering spinal injuries, selection would have favored the evolution of psychological mechanisms in men to prefer women exhibiting cues to these spinal structures. Men could not directly observed women's vertebrae, but lumbar curvature is an externally visible cue to the relevant spinal structures.
At this point, we had a hypothesis that was both anchored in evolutionary theory and grounded in medical orthopedic literature. It was time we tested our idea that men possess a previously undiscovered, evolved preference for a beneficial intermediate angles of lumbar curvature in women.
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MedicalResearch.com Interview with:Pedram Gerami MD
Associate Professor of Dermatology and Pathology
Northwestern University
MedicalResearch: What is the background for this study? What are the main findings?Dr. Gerami: The outcomes for patients with cutaneous melanoma are highly variable and there are limitations to the conventional staging system for melanoma. For example while the status of the sentinel lymph node biopsy is considered the strongest prognosticator, approximately 2/3 of cutaneous melanoma patients that ultimately die from their melanoma will have a negative sentinel lymph node biopsy result. In this study we showed that using a technique known as mRNA expression profiling to determine which genes are highly active and which are not that a molecular prognostic assay with accuracy could be developed. This assay can accurately classify patients based on their gene signature as having a high or low risk for metastasis and death from their melanoma. In an independent validation cohort, patients with a class I or low risk signature had a 5 year disease free survival rate of 97% while those with a class II or high risk signature had a 5 year disease free survival rate of only 31%.
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MedicalResearch.com Interview with:
Dr. Michaela A. Dinan Ph.D
Department of Medicine
Duke University
Medical Research: What is the background for this study? What are the main findings?
Dr. Dinan: We wanted to examine how Oncotype DX® Breast Cancer Test (ODX) was being used in real-world practice at the population level. ODX has been examined in clinical trials and limited academic settings but we know that these patients are often younger, have fewer medical comorbidities, and do not necessarily accurately reflect the majority patients with cancer. In our study, we observed that Oncotype DX® Breast Cancer Test was being used predominately in accordance with guidelines which recommend the test for women with estrogen-receptor positive, disease. We also looked just at women under the age of 70 who met guideline criteria for testing, because this population would include those women who were more likely to be chemotherapy candidates, and we saw a rapid uptake of the test between 2005 and 2009, with use of the test increasing from 8% to 39%.
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MedicalResearch.com Interview with:
Fernando Pardo-Manuel De Villena, PhD
Professor and Associate Chair for Research
Department of Genetics
School of Medicine
University of North Carolina at Chapel Hill
Medical Research: What is the background for this study? What are the main findings?Response: We set out to identify mutations that affect diseases through changes in gene expression. Our first major finding is that some mouse populations such as the Collabaorative Cross are exceptionally good models to achieve this goal.
We also wanted to sort out an ongoing controversy about the number, location and type of genes that are differentially expressed when you inherit them from your mom or your dad (so called imprinted genes). We conclude that to some extent both sides were right; there are only a limited number of imprinted genes in the classical sense but there are also hundreds or thousands of genes that are preferentially expressed from the father.
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MedicalResearch.com Interview with:
Linda Chin, MD
Department Chair, Department of Genomic Medicine, Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, TX
Medical Research: What is the background for this study? What are the main findings?
Dr. Chin: BRAF inhibitors have worked very well against melanoma in the clinic, but when the tumors relapse on treatment, it is not always clear what causes it. Without this information, it can be difficult for doctors to identify specific second-line therapies likely to overcome the drug resistance. In this study, we used both mouse and patient melanoma samples to identify patterns of selected protein levels that can categorize modes of drug resistance when other assays such as DNA sequencing are uninformative. We hope that this information can provide missing clues for clinicians. (more…)
Dr. Liming Liang PhD
Assistant Professor of Statistical Genetics
Departments of Epidemiology and Biostatistics,
Harvard School of Public Health, Boston, Massachusetts
Allergies affect...
MedicalResearch.com Interview with:
Dr. Peter Forster PhD
Fellow of Murray Edwards College and
McDonald Institute at the University of Cambridge
Medical Research: What is the background for this study? What are the main findings?Dr. Forster: As a result of our paternity testing work at the Institute for Forensic Genetics in Munster (Germany), we have accumulated a pool of over 24,000
parents and their children, of whom we know for certain that they are
biologically related. Occasionally we observe a new mutation in these
children, which must have come either from the sperm or the egg of one
of the parents. As we analyse highly variable microsatellite DNA (a
repetitive type of DNA, also know as STR DNA, which stands for "short
tandem repeat" DNA), we can fairly easily find out whether the mutation
has come from the mother or the father. It turns out that the fathers
contribute 6-7 times more mutations to the children than the mothers do.
This has long been known. What is new is that we have observed that the
male and female teenagers at puberty do NOT set out with the same low
mutation load, but instead, the teenage boys already have a sixfold
higher mutation load in their sperm than the girls in their oocytes. (more…)
MedicalResearch.com Interview with: Dr. Rahul S. Desikan MD, PhD
Department of RadiologoyUniversity of California, San Diego School of Medicine
Medical Research: What is the background for this study? What are the main findings?
Dr. Desikan: The MAPT gene encodes the tau protein, which plays an integral role in Alzheimer's disease (AD) neurodegeneration. Though a number of studies have investigated this issue, the role of the MAPT gene in Alzheimer's disease is still unclear. In contrast, a number of studies have found a robust association between MAPT and increased risk for other 'tauopathies' like Parkinson's disease (PD). In our study, rather than evaluating all possible genetic loci, we only assessed shared genetic variants between Alzheimer's disease and PD. By using this type of approach, we were able to increase our statistical power for gene discovery in Alzheimer's disease.
We found genetic overlap between Alzheimer's disease and Parkinson's disease at a locus on chromosome 17 within the MAPT region. Our findings demonstrate that this MAPT associated locus increases risk for Alzheimer's disease, correlates with gene expression of MAPT and is associated with brain atrophy of the entorhinal cortex and hippocampus on longitudinal MRI scans.
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MedicalResearch.com Interview with:
Prof. Jozef Gecz
NH&MRC Senior Principal Research Fellow
Professor of Human Genetics
School of Paediatrics and Reproductive Health
Faculty of Health Sciences The University of Adelaide at the Women's and Children's Hospital North Adelaide, SA Medical Research: What is the background for this study? What are the main findings?
Prof. Gecz: Cerebral palsy is the most frequent movement disorder of children for many years considered to be due to brain injury. Given that cerebral palsy incidence has not changed dramatically over many years while medical care is constantly improving, we look for other causes and specifically genetic mutation. By investigating 183 children with cerebral palsy and for many also one or both of their parents we find that for at least 14% of these we can find plausible explanation in genetic mutation being involved in the causation of their cerebral palsy. Importantly, we find that 10% of these mutations are de novo, which means that these mutations are not present in the parents (specifically in their blood as that is the tissue source we tested). 4% of mutations were inherited from unaffected mothers to affected sons. Previous estimates suggested 2% genetic contribution to Cerebral palsy. We now know that it is at least 14% and likely more. If you are looking for compensation for this condition, contact an Indiana cerebral palsy lawyer.
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MedicalResearch.com Interview with:
David G. Kent, Ph.D
From the Cambridge Institute for Medical Research and Wellcome Trust–Medical Research Council Stem Cell Institute University of Cambridge
Medical Research: What is the background for this study? What are the main findings?
Dr. Kent: Cancers are the result of the sequential acquisition of errors in the genetic code. Most studies have focused on the sum of these mutations (e.g., A+B+C = cancer) but no study in patients has asked the question of whether or not the order of genetic mutations impacts the disease (e.g., does A to AB equal B to BA). We studied patients with chronic blood disorders (known as myeloproliferative neoplasms, or MPNs) that are precursors to cancer to access the earliest stages of tumour development and studied whether or not the order of mutation acquisition impacted disease. We studied patients with mutations in two genes (JAK2 and TET2) and showed that the order of acquisition of these mutations impacted timing of clinical presentation, disease subtype, frequency of thrombotic events, and differed in their response to targeted therapy in the lab. (more…)
MedicalResearch.com Interview with:Wolfgang Sadee, Dr.rer.nat.
Felts Mercer Professor of Medicine and Chair, Pharmacology Director
and Elizabeth S Barrie, PhD
Center for Pharmacogenomics
The Ohio State University Columbus OH
MedicalResearch: What is the background for this study? What are the main findings?Dr. Sadee and Dr. Barrie: We have determined that two frequent genetic variants can interact in a way that lowers the carrier’s risk for a heart attack. These genetic variants are single nucleotide polymorphisms (SNPs) - single base changes in the DNA sequence - of the dopamine-beta hydroxylase gene (DBH), which converts dopamine to norepinephrine. Both act as hormones in the periphery and as neurotransmitters vital to the brain's activity central nervous system. Numerous studies had tested genetic variants in DBH for effects on brain functions. In contrast to expectations, however, our work demonstrates that our two genetic variants lower DBH activity primarily in the periphery, in tissues with sympathetic innervation mediated by norepinephrine, such as the heart, lung, and liver. As a result, we searched for genetic influence on risk of various diseases of the cardiovascular system and the lung, metabolic disorders, and more. Each of the two DBH variants alone was associated with a number of disease states; however, when considering both variants in combination, a strong protective effect on the risk for heart attacks was discovered in several clinical trials. Such combined effects arising from interactions between two genetic variants may be more common than currently realized, possibly providing a path towards effective biomarker panels for personalized medicine. (more…)
MedicalResearch.com Interview with:
Andres Moreno De Luca, MD
Investigator and Resident Physician
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: The main finding of our study is that family background contributes to the variability in cognitive, behavioral, and motor performance seen in children with 16p11.2 deletions, and perhaps other genetic syndromes, and this may be attributed in part to genetic background effects.
In the general population the best predictor of a child’s outcomes in traits such as cognitive ability, height, BMI, etc. is the biparental mean performance in such domains and this is due in part to genetic background. For example, if a child’s parents have IQ scores of 130 and 110, it is expected that the child will have an IQ within 2 standard deviations of 120 (bi-parental mean). However, when studying individuals with genetic conditions, most researchers tend to overlook the influence of familial/genetic background on the affected child’s outcomes and commonly attribute the manifestations (or lack thereof) to the genetic mutation alone.
This creates confusion when studying children with neurodevelopmental disorders, such as autism, which show significant clinical variability, as some children with a specific genetic mutation (e.g. deletion 16p11.2) may have intellectual disability without autism, while other children with the same mutation may have autism without intellectual disability. Based on these observations, some researchers have argued that deletion 16p11.2 is incompletely penetrant. However, our study showed that the 16p11.2 deletion has a detrimental effect on cognitive and behavioral performance for all children, but the clinical status (affected vs. unaffected) and ultimate performance level is influenced by the parental performance.
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MedicalResearch.com Interview with: Professor Anne Barton FRCP PhD and
Dr John Bowes PhD
Centre for Musculoskeletal Research and
Centre for Genetics and Genomics,
The University of Manchester, Manchester UK
Medical Research: What is the background for this study?
Response: Psoriatic arthritis (PsA) is an inflammatory condition causing pain and stiffness in joints and tendons. Approximately one third of patients with psoriasis will go on to develop PsA resulting in a reduction in their quality of life caused by increasing disability and additional health complications. A key area of research within the Arthritis Research UK Centre for Genetics and Genomics in the Centre for Musculoskeletal Research is the identification of risk factors for the development of Psoriatic arthritis; this will allow us to understand the underlying cause of disease and ultimately help identify psoriasis patients at high risk of PsA, allowing early treatment to be introduced to reduce the impact of PsA.
Our study focuses on the identification of genetic risk factors for Psoriatic arthritis; we compared the frequency of genetic variants, referred to as single nucleotide polymorphisms (SNPs), between large numbers of DNA samples from patients with PsA and healthy control samples. When the frequency of the SNP is significantly different between cases and controls, the SNP is said to be associated with risk of developing Psoriatic arthritis and this association is interpreted as being important in the disease process.
Medical Research: What are the main findings?
Response: When we analysed the data from the study we found a new association to SNPs on chromosome 5, and when we investigated these SNPs for association with skin-only psoriasis, we did not find any evidence for association. In addition, we also found SNPs that were specifically associated with Psoriatic arthritis at a gene on chromosome 1. This gene is known to be associated with psoriasis, but our results show that there are different SNPs associated with PsA and psoriasis at this gene. Hence, our results identify new SNPs that are specifically associated with PsA.
In addition, identifying which cells are the key drivers of inflammation in Psoriatic arthritis will help us to focus on how the genetic changes act in those cells to cause disease. Our results show that many of the PsA associated SNPs occur in regions of the genome that are important in the function of CD8+ cells, an important cell type in the immune system.
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MedicalResearch.com Interview with:
Peter White, Ph.D.
Principal Investigator, Center for Microbial Pathogenesis
Director, Biomedical Genomics Core
Director of Molecular Bioinformatics, The Research Institute at Nationwide Children's Hospital
Assistant Professor of Pediatrics, The Ohio State University
Medical Research: What is the background for this study? What are the main findings?
Dr. White: Next generation sequencing has revolutionized genomics research and has opened the door to a new era of genomic medicine. It’s now possible to sequence a patients entire genome in about two days, but the output from the sequencer must go through multiple computationally challenging steps before it can be processed for clinically relevant information. The challenge we found is that this data analysis process was requiring days to perform, by highly qualified bioinformaticians and required enormous computational resources.
To overcome the challenges of analyzing that large amount of genomic sequence data, we developed a computational pipeline called “Churchill”, which we published in the latest issue of Genome Biology (http://genomebiology.com/2015/16/1/6/abstract). Churchill fully automates the analytical process required to take raw sequence data through a series of complex and computationally intensive processes, ultimately producing a list of genetic variants ready for clinical interpretation and tertiary analysis. The major impact of our work was the development of a novel balanced parallelization strategy that allows efficient analysis of a whole genome sequencing sample in as little as 90 minutes.
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MedicalResearch.com Interview with:
Dr. John Ramunas PhD
Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Clinical Sciences Research Center, Stanford University School of Medicine, Stanford, CaliforniaMedical Research: What is the background for this study?
Dr. Ramunas: Telomeres comprise repetitive DNA sequences at the ends of chromosomes. Telomeres protect the ends of chromosomes, but become shorter with each cell division and due to oxidative damage. Critically short telomeres are implicated in diseases of aging and devastating genetic disorders of insufficient telomere maintenance .
Medical Research: What are the main findings?
Dr. Ramunas: Our main finding is that telomeres in human cells can be lengthened by a new method with therapeutic potential. We delivered modified mRNA encoding TERT, the protein component of telomerase, the enzyme that increases the length of telomeres by adding DNA repeats. The protein TERT is usually the rate limiting component of the enzyme. In this study, we used four groups of cells. The first group received modified mRNA encoding TERT, and the other three groups were controls that received either mRNA encoding an inactive form of TERT, the solution in which TERT is delivered, or no treatment. The telomeres of the first group (telomere extending treatment group) were extended rapidly over a period of a few days, whereas the telomeres of the three control groups were not extended. The first group was also able to undergo more cell divisions, whereas the controls were not. Importantly for the potential safety of our approach, the telomeres of the first group resumed shortening after they were extended. This is important because it shows that due to the short, transient treatment, the cells were not immortalized, ie. not tumorigenic. Further, all of the cell populations treated to date eventually stopped dividing, further indicating that they were not immortalized. We have tested the approach on cell types including fibroblasts and myoblasts and are now testing it on stem cells. A surprising and exciting finding was that we could treat the cells several times with enhanced effects on the capacity of cells to divide. For instance, after a first treatment, we saw an increase of 50,000-fold in cell numbers before cells stopped dividing, compared to untreated cells. If we waited a few weeks and repeated this treatment, we saw a similar gain in cell division and number. Since the increase in numbers is compounded with each treatment, a small sample of cells, for example from a small biopsy, can be amplified to very large numbers. (more…)
MedicalResearch.com Interview with:
Joao Pedro de Magalhaes, PhD
Institute of Integrative Biology
Biosciences Building, Room 245
University of Liverpool UK
Integrative Genomics of Ageing Group: http://pcwww.liv.ac.uk/~aging/Medical Research: What is the background for this study? What are the main findings?Response: Our understanding of species differences in longevity (e.g., why can mice not live more than 5 years or dogs more than 30, yet bats can live over 40 years, humans over a century and bowheads over two centuries) is very poor and thus our findings provide novel candidate genes and mechanisms for future studies. The candidate genes we found with evidence of bowhead-specific functions may play a role in the exceptional longevity and disease resistance of these animals. In particular, we discovered changes in bowhead genes related to cell cycle, DNA repair, cancer, and aging that suggest alterations that may be biologically-relevant. So my own view is that this points toward improved DNA repair and cell cycle regulation mechanisms to prevent DNA damage accumulation during the lifescourse which in turn promotes longevity and resistance to age-related diseases like cancer.
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MedicalResearch.com Interview with:
Stephen F. Kingsmore MB ChB BAO DSc FRCPath
Dee Lyons/Missouri Endowed Chair in Genomic Medicine,
Children’s Mercy - Kansas City
Medical Research: What is the background for this study?
Response: The background to this study is that genetic diseases are the leading cause of death in infants and, especially, in infants in neonatal intensive care units. Making a molecular (etiologic) diagnosis of the specific genetic disease is critical for optimal care and decision making for acutely ill infants who are likely to have such diseases. However there are over 5000 known genetic diseases and their presentations overlap considerably in infants. Until now it has not been possible to make timely diagnoses in these infants.
Medical Research: What are the main findings?
Response: Rapid whole genome sequencing is a new way of making a genetic disease diagnosis in acutely ill newborns in neonatal intensive care units. It appears to be effective for diagnosis.
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