Author Interviews, Genetic Research, Karolinski Institute, Nature, Neurological Disorders / 11.05.2015

MedicalResearch.com Interview with: Kristina Bečanovič Ph.D. Department of Clinical Neuroscience Karolinska Institutet, Stockholm, Sweden Medical Research: What is the background for this study? Dr. Bečanović: While the symptoms normally debut in middle-age, there is wide individual variation in how Huntington disease manifests itself, and even though two people carry the exact same genetic mutation that codes for the huntingtin protein, there can be up to a 20-year difference in onset of motor symptoms. This suggests that genetic variants, transcription factors and environmental factors could contribute to the observed differences in disease expressivity. As the identification of regulatory factors of the huntingtin gene would be targets for therapeutic intervention, we set out to study the regulation of the huntingtin gene as it has not been well-known which factors regulate the expression levels. We were interested in identifying both genetic variants and transcription factors that are of importance for gene regulation. We therefore used DNA from Huntington disease patients to study the regulation of the huntingtin gene promoter in cells. (more…)
Author Interviews, Breast Cancer, JNCI, Surgical Research / 11.05.2015

Bernadette A.M. Heemskerk-Gerritsen, Ph.D. Department of Medical Oncology Erasmus MC Cancer Institute Roterdam, the NetherlandsMedicalResearch.com Interview with: Bernadette A.M. Heemskerk-Gerritsen, Ph.D. Department of Medical Oncology Erasmus MC Cancer Institute Roterdam, the Netherlands Medical Research: What is the background for this study? What are the main findings? Dr. Heemskerk-Gerritsen: Women with a BRCA1 or BRCA2 mutation have substantially higher risks of developing both primary and contralateral breast cancer (BC) and ovarian cancer than women from the general population. Options to reduce these increased cancer risks include risk-reducing mastectomy (RRM) and/or risk-reducing salpingo-oophorectomy (RRSO). The latter intervention obviously reduces the risk of developing ovarian cancer, but has been reported also to reduce the risk of developing a subsequent breast cancer with approximately 50%. However, studies on the efficacy of risk-reducing surgery in BRCA1/2 mutation carriers are confined to observational studies, thus challenging several methodological issues. Consequently, previous studies on breast cancer risk-reduction after RRSO may have been influenced by bias associated with selection of study subjects, bias associated with start of follow-up, or by confounding, and breast cancer risk-reduction may have been overestimated. In the current study, we revisited the association between risk-reducing salpingo-oophorectomy and breast cancer risk in BRCA1/2 mutation carriers, focusing on the impact of different analytical methods and potential types of bias. First, we replicated the analyses of four previously performed studies, to examine if our Dutch cohort was comparable with the cohorts used in the previous studies. We replicated the approximately 50% breast cancer risk reduction after RRSO in the Dutch cohort. Second, we estimated the effect of RRSO on breast cancer risk in the Dutch cohort using a revised analytical approach for observational studies in BRCA1/2 mutation carriers in order to minimize bias as much as possible. Using this method of analysis, we found no evidence of first BC risk-reduction after RRSO in BRCA1/2 mutation carriers. (more…)
Author Interviews, Genetic Research / 09.05.2015

Rebecca Todd Ph.D. Assistant Professor University of British Columbia Department of Psychology Centre for Interactive Research on Sustainability Vancouver, BCMedicalResearch.com Interview with: Rebecca Todd Ph.D. Assistant Professor University of British Columbia Department of Psychology Centre for Interactive Research on Sustainability Vancouver, BC Medical Research: What is the background for this study? What are the main findings? Dr. Todd: This study brings together two lines of research. First, a couple of years ago my colleagues and I reported that in general people literally see emotional aspects of the world as more vivid - as if they burn more brightly on the eye - than mundane things. We call this effect emotionally enhanced vividness, or EEV. Here we wanted to look at how this phenomenon of emotionally enhanced vividness might differ between individuals. Second, in another previous study we found that people who carry a very common variation in the ADRA2b gene, which influences levels of norepinephrine (a neuromodulator in the brain that is important to the stress response and for emotional influences on memory) were more likely to have their attention captured by emotionally relevant aspects of the world. We also found that how arousing they perceived an event to be at the time it happened predicted how well they remembered it better than for people who did not carry this variation. Here we continued to examine what is unique to this group of people by testing to see if they showed higher levels of the other phenomenon we had found, emotionally enhanced vividness, and what patterns of brain activation would play a role. (more…)
Author Interviews, Breast Cancer, Case Western, Genetic Research / 07.05.2015

Ahmad M. Khalil, PhD Assistant professor, Department of Genetics and Genome Sciences Case Western Reserve University School of MedicineMedicalResearch.com Interview with: Ahmad M. Khalil, PhD Assistant professor, Department of Genetics and Genome Sciences Case Western Reserve University School of Medicine MedicalResearch: What is the background for this study? What are the main findings? Dr. Khalil: This study aimed to identify other genes that work synergistically with the oncogene HER2 in HER2positive (HER+) breast cancer. The gene HER2 is amplified in those patients, which results in excess activities that promote uncontrolled cell growth. There are drugs that target HER2 and diminish its activity. However, these drugs can work initially, but patients relapse; or sometimes, the drugs don't work at all in some patients. Thus, by identifying other genes that work synergistically with the HER2 gene, we now have more genes to target by various drugs or compounds to destroy the tumor. The challenge was how to identify the key genes that work synergistically with HER2, especially in human subjects. To that end, we used clinical samples from a clinical trial of a drug that is known to inhibit HER2 activity to identify those genes. To further refine our list, we used cell culture models of the disease to also inhibit HER2. By combining those data sets, we identified 44 protein-coding genes. Next, we wanted to make sure that those genes stand a third independent filter. For that part, we interrogated those 44 genes in HER2+ tumors vs matched normal tissues from The Cancer Genome Atlas database — a collection of hundreds of tumors and normal tissues. Of the 44 genes, 35 genes passed this third filter. By examining the known functions of those genes, we can deduce that those genes work cooperatively with HER2 to promote carcinogenesis. There are currently known drugs that target some of those genes. We will use these drugs in combination with a drug that target HER2 to determine if the combination works better at destroying the tumor entirely. Lastly, we found that a special type of genes that we previously discovered, called lincRNAs, could also affect the oncogenic activity of HER2. These lincRNAs can also be targeted with HER2 to eliminate the tumor. (more…)
Author Interviews, Genetic Research, NEJM, Ophthalmology / 05.05.2015

Professor James Bainbridge, MA, PhD, FRCOphthProfessor of Retinal Studies, UCL Institute of Ophthalmology NIHR Research Professor, NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of OphthalmologyMedicalResearch.com Interview with: Professor James Bainbridge, MA, PhD, FRCOphth Professor of Retinal Studies, UCL Institute of Ophthalmology NIHR Research Professor, NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of OphthalmologyConsultant Ophthalmologist, Moorfields Eye Hospital NHS Foundation Trust Medical Research: What is the background for this study? What are the main findings? Prof. Bainbridge : Leber Congenital Amaurosis (LCA) is one of the most common causes of inherited, untreatable blindness in children. There are at least 14 different types of Leber Congenital Amaurosis of which LCA Type 2 (LCA2), caused by defects in the gene RPE65, affects around one in 100,000 people worldwide. Evidence from animal studies support that LCA2 may be amenable to treatment with RPE65 gene replacement therapy. The main findings of this phase I/II clinical trial confirm our preliminary findings (published in NEJM, 2008) that gene therapy can improve night vision. Improvements peak within the first 12 months after treatment but then decline during the three-year follow-up period which is consistent with the published results and interim findings from other studies of RPE65 gene therapy. (more…)
Author Interviews, Cancer Research, Gastrointestinal Disease, Genetic Research, NIH / 30.04.2015

Dr. Steven Wank MDMedicalResearch.com Interview with: Dr. Stephen Wank MD Digestive Diseases Branch, NIDDK National Institutes of Health, Bethesda, Maryland MedicalResearch: What is the background for this study? Dr. Wank: Small intestinal carcinoids are rare and difficult to diagnose because symptoms may be absent or mistaken for more common diseases. Because carcinoids usually grow slowly over several years before spreading or causing symptoms, patients often seek medical attention late with advanced, incurable disease. However, when diagnosed at an early stage, carcinoid can be surgically cured. Presently, there are no long-term effective therapies for surgically non-resectable disease. Although carcinoids occur sporadically, there have been reports of family clusters (more than one blood relative with carcinoid). Hereditary small intestinal carcinoid has not been recognized as a disease and causative genetic factors have not been identified in either sporadic cases or families with multiple affected members. If small intestinal carcinoid occurs in families on a hereditary basis, we hypothesized that asymptomatic relatives in families with carcinoid are at a high risk of harboring an undiscovered tumor. To test this, we established a clinical research protocol at the National Institutes of Health in Bethesda, Maryland to screen asymptomatic relatives in families with at least two cases of small intestinal carcinoid in the hope of detecting their tumors at an early surgically curable stage. If successful in our endeavor, we would improve the outcome of the disease in these asymptomatic relatives and position ourselves to discover the genetic basis for their disease. Understanding the gene mutations causing small intestinal carcinoid would allow us to screen for the disease with a blood test, help us understand what causes the disease, and treat the disease with specific targeted therapies. (more…)
Author Interviews, Genetic Research, Lancet, Pediatrics / 29.04.2015

MedicalResearch.com Interview with: Stephen F. Kingsmore MB ChB BAO DSc FRCPath Dee Lyons/Missouri Endowed Chair in Genomic Medicine, Children’s Mercy - Kansas CityMedicalResearch.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. (more…)
Author Interviews, Breast Cancer, Genetic Research / 27.04.2015

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, UKMedicalResearch.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. (more…)
AACR, Author Interviews, Genetic Research, Melanoma, NYU, Personalized Medicine, Wistar / 21.04.2015

Melissa Wilson, MD, PhD Assisstant Professor Perlmutter Cancer Center NYU Langone Medical Center New York, NYMedicalResearch.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. (more…)
Author Interviews, Genetic Research, Nature, Pancreatic, UT Southwestern / 10.04.2015

Dr. Agnieszka Witkiewicz MD Associate Professor of Pathology Harold C. Simmons Comprehensive Cancer Center UT SouthwesternMedicalResearch.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. (more…)
Author Interviews, Genetic Research, JAMA, Melanoma / 10.04.2015

Nancy E. Thomas, MD, PhD Department of Dermatology University of North CarolinaMedicalResearch.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…)
Author Interviews, Case Western, Genetic Research / 20.03.2015

Jeff Coller, PhD Associate professor Division of General Medical Science Associate director, The Center for RNA Molecular Biology, Case Western Reserve University School of MedicineMedicalResearch.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. (more…)
Author Interviews, Genetic Research, Race/Ethnic Diversity / 17.03.2015

Jay S. Kaufman, Ph.D Canada Research Chair in Health Disparities Department of Epidemiology, Biostatistics, and Occupational Health McGill University Montreal, Quebec CANADAMedicalResearch.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. (more…)
Author Interviews, Colon Cancer, Genetic Research, JAMA / 12.03.2015

Matthew B. Yurgelun, MD Instructor in Medicine Harvard Medical SchoolMedicalResearch.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…)
Author Interviews, Genetic Research, McGill, Nature / 12.03.2015

Prof. Moshe Szyf Ph.D. James McGill Professor of Pharmacology and Therapeutics McGill UniversityMedicalResearch.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. (more…)
Author Interviews, Genetic Research, Melanoma, Personalized Medicine / 08.03.2015

Pedram Gerami MD Associate Professor of Dermatology and Pathology Northwestern UniversityMedicalResearch.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%. (more…)
Author Interviews, Dermatology, Melanoma / 06.03.2015

MedicalResearch.com Interview with: Alberto Pappo, M.D. Member, Oncology; Director, Solid Tumor Division St. Jude Children’s Research Hospital Medical Research: What is the background for this study? What are the main findings? Dr. Pappo: Researchers have identified three distinct subtypes of childhood and adolescent tumors of pigment-producing skin cells called melanocytes. The subtypes have different genetic alterations and often different outcomes for patients. The findings should aid efforts to improve diagnosis and treatment of melanoma, which is the most common skin cancer in children and adolescents. The study provides the most comprehensive analysis yet of the genetic alteration underlying pediatric melanoma, including the first genetic evidence that sun damage causes melanoma in children and adolescents as well as adults. Researchers used whole genome sequencing and other techniques to study the normal and cancer genomes of 23 young patients with a variety of melanocytic tumors, including conventional melanoma. Patients ranged in age from 9 months to 19 years old. The melanoma subtypes in this study included conventional melanoma, which scientists showed was the same disease in children, adolescents and adults. More than 90 percent of pediatric conventional melanoma had DNA changes linked to sun damage. (more…)
Author Interviews, Genetic Research, Nature / 04.03.2015

Fernando Pardo-Manuel De Villena, PhD Professor and Associate Chair for Research Department of Genetics School of Medicine University of North Carolina at Chapel HMedicalResearch.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. (more…)
Genetic Research, MD Anderson, Melanoma, Personalized Medicine / 04.03.2015

Linda Chin, MD Department Chair, Department of Genomic Medicine, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TXMedicalResearch.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…)
Author Interviews, Genetic Research, JAMA / 20.02.2015

Dr. Peter Forster PhD Fellow of Murray Edwards College and McDonald Institute at the University of CambridgeMedicalResearch.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…)
Author Interviews, Breast Cancer, NEJM / 19.02.2015

  Swain_SandraMedicalResearch.com Interview with: Sandra M Swain, MD, FACP, FASCO Medical Director, Washington Cancer Institute MedStar Washington Hospital Center Washington DC 20010 MedicalResearch: What take-home message would you like the general public to understand about this new analysis from the Cleopatra study? Potential Key Message Options:
  • Updated results from the CLEOPATRA study showed that people treated with the combination of pertuzumab, trastuzumb and chemotherapy lived 15.7 months longer than those who received trastuzumab and chemotherapy alone (median survival of 56.5 months versus 40.8 months).
  • The survival improvement of nearly 16 months observed in CLEOPATRA is unprecedented among studies of metastatic breast cancer. This is the kind of survival improvement that those of us who treat breast cancer strive for, and this data will be incredibly meaningful to patients and their families.
  • Furthermore, the median survival of nearly five years observed in CLEOPATRA patients treated with the pertuzumab regimen is the longest ever observed in a clinical study of people with HER2-positive metastatic breast cancer, once one of the most aggressive forms of breast cancer.
  • Patients who responded with shrinkage of their tumor had a response that was 8 months longer with the pertuzumab regimen compared to the trastuzumab and chemotherapy regimen.
(more…)
Author Interviews, Genetic Research, UCSD / 18.02.2015

Dr. Rahul S. Desikan MD, PhD Department of Radiologoy University of California, San Diego School of MedicineMedicalResearch.com Interview with: Dr. Rahul S. Desikan MD, PhD Department of Radiologoy University 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. (more…)
Author Interviews, Genetic Research, Personalized Medicine / 13.02.2015

Prof. Jozef GECZMedicalResearch.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. (more…)
Author Interviews, Genetic Research, Leukemia, NEJM, Personalized Medicine / 11.02.2015

David G. Kent, Ph.D From the Cambridge Institute for Medical Research and Wellcome Trust–Medical Research Council Stem Cell Institute University of CambridgeMedicalResearch.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…)
AHA Journals, Author Interviews, Genetic Research, Heart Disease / 10.02.2015

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…)
Author Interviews, Genetic Research, JAMA, Personalized Medicine / 09.02.2015

Andres Moreno De Luca, MD Investigator and Resident Physician Autism & Developmental Medicine Institute Department of Radiology Geisinger Health System Danville, PA 17822MedicalResearch.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. (more…)
Author Interviews, Genetic Research, Nature, Rheumatology / 06.02.2015

psoriasis_kneesMedicalResearch.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. (more…)