Author Interviews, Cancer Research, Colon Cancer, Genetic Research, Nature / 18.10.2022 Interview with: Royce Zhou, MD/PhD Candidate Icahn School of Medicine at Mount Sinai What is the background for this study? Response: The background of this story is to see whether things outside of the cancer cell, such as the tumor microenvironment, can lead to epigenetic changes within the cancer cell. These changes are largely believed to be due to factors inside the cell, not outside. Super-enhancers are the top 1-2% of enhancers in the genome. They control cell identity genes and oncogenes in cancer. (more…)
Author Interviews, Exercise - Fitness, Genetic Research, Lifestyle & Health, Nature / 08.09.2022 Interview with: Marcel den Hoed, PhD Researcher,Department of Immunology, Genetics and Pathology Uppsala University What is the background for this study? What are the main findings? Response: In this paper we performed a multi-ancestry meta-analysis of 51 genome-wide association studies, in data from over 700,000 individuals. This yielded 11 DNA regions that are robustly associated with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), and 88 DNA regions for self-reported leisure screen time (LST). Around half of the identified DNA regions are also associated with objectively assessed physical activity traits in data from the UK Biobank. Causal inference using a Mendelian randomization approach subsequently showed bidirectional causal effects between LST and body mass index (BMI), with the effect of LST on BMI being 2-3-fold larger than vice versa. Less LST and more MVPA protect from diabetes, attention deficit hyperactivity disorder, depression, and earlier age at death, with all causal effects of MVPA and leisure screen time being mediated or confounded by BMI. Further analyses showed that DNA regions associated with LST are more often located close to genes whose expression in skeletal muscle is altered by strength training than expected by chance, suggesting that these genes may influence the likelihood of adopting an active lifestyle by influencing the response to training. (more…)
Author Interviews, Genetic Research, Heart Disease / 04.08.2022 Interview with: Christine Seidman, MD Thomas W. Smith Professor of Medicine and Genetics Director, CV Genetics Center Brigham and Women’s Hospital Harvard Medical School Dept of Genetics Boston, MA 02115  What is the background for this study?    Response: Heart failure is a common and incurable disorder that is known to arise from many different underlying causes.  By exploiting a new technology, single nuclear transcriptional analyses, we aimed to define molecular profiles in human hearts tissues that were obtained from patients with different genetic and non-genetic causes of heart failure. Our goal was to determine if there were distinctive signatures that could provide new opportunities to develop precise treatments, based on the specific cause of heart failure. (more…)
Author Interviews, Diabetes, Genetic Research, Herpes Viruses / 12.05.2022 Interview with: Prof. Annette Peters PhD Chair of Epidemiology Institute of Medical Information Sciences, Biometry and Epidemiology, Ludwig-Maximilians University Munich, Germany Institute of Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany German Center for Diabetes Research (DZD), München-Neuherberg, Germany  What is the background for this study?  What are the main findings? Response: A large number of genetic, behavioural and environmental risk factors have been identified as contributing to the risk of type 2 diabetes. However, little is known about a potential link between virus infections and type 2 diabetes developments. We had the unique opportunity to use a multiplex assay to measure antibodies for herpes viruses by the Waterboer laboratory at the German Cancer Center in Heidelberg and set out to investigate the potential associations in the prospective KORA cohort. First of all, we detected that herpes virus antibodies were highly prevalent in the study population at baseline and increased with age. We found an association between Herpes simplex virus 2 and cytomegalovirus and type 2 diabetes during a seven year follow-up. These associations were robust against controlling for other known risk factors. (more…)
Aging, Alzheimer's - Dementia, Author Interviews, Brigham & Women's - Harvard, Genetic Research, Nature / 20.04.2022 Interview with: Michael B. Miller, MD, PhD Instructor, Harvard Medical School Department of Pathology Brigham and Women's Hospital  What is the background for this study? Would you explain what is meant by somatic genetic changes and how they might occur?  Response: Changes, also called mutations, in the DNA sequence of genes can be passed from parents to their children, and explain why many diseases run in families. This kind of DNA change is called a germline mutation and is present in every cell in a person’s body. Gene mutations can also occur in a subset of cells of a person, in which case they are called somatic mutations. Somatic mutations are well known as a cause of cancer, and recent research has found that somatic mutations can also happen in non-cancerous cells that appear otherwise normal. Recent studies have even found that somatic mutations are present in neurons, cells in the brain that transmit electrical signals and play an important role in how the brain functions. Furthermore, in neurons, somatic mutations increase with age, so we set out to understand if somatic mutations might be playing a role in age-related brain diseases like Alzheimer’s. (more…)
Author Interviews, Brigham & Women's - Harvard, Cancer Research, Genetic Research, Nature / 18.04.2022 Interview with: Jason Vassy, MD, MPH Brigham and Women's Hospital Division of General Internal Medicine & Primary Care Brigham’s Precision Population Health at Ariadne Labs and VA Boston  What is the background for this study?    Response: A person’s risk of developing diseases such as type 2 diabetes or breast cancer may be influenced by thousands of genetic differences, the effects of which can be combined to derive a single score, often called a polygenic risk score (PRS). PRS might be useful to help patients and their physicians make tailored decisions about their health care, but several challenges to the clinical implementation of PRS remain. Most importantly, most PRS are less accurate in individuals of non-European descent, since most genomic research to date has been conducted in European populations. Another key challenge is that physicians and patients will need support to understand polygenic risk score and use them to make medical decisions. Clinical guidelines do not yet exist to help a physician know whether and how they should treat a patient with a high-risk score differently than an average-risk patient. We designed the Genomic Medicine at VA (GenoVA) Study to address some of these challenges. (more…)
Author Interviews, Genetic Research, Sleep Disorders, UCSF / 20.03.2022 Interview with: Ying-Hui Fu, PhD Professor, Neurology Weill Institute for Neurosciences UCSF  What is the background for this study?  Response: Most people are aware that a lack of sleep is associated with all sorts of health issues. However, familial natural short sleeper (FNSS) individuals sleep 4-6.5 hours a night most of their live and stay healthy. We set out to determine whether natural short sleep mutations can offer protection from various diseases. We chose Alzheimer as an example to start. (more…)
Author Interviews, Genetic Research, Heart Disease, Technology / 17.03.2022 Interview with: Ali Torkamani, Ph.D. Director of Genomics and Genome Informatics Scripps Research Translational Institute Professor, Integrative Structural and Computational Biology Scripps Research La Jolla, CA 92037  What is the background for this study?  Response: Prior research has shown that people with higher polygenic risk for coronary artery disease achieve greater risk reduction with statin or other lipid lowering therapy. In general, adherence to standard guidelines for lipid lowering therapy is low - about 30% of people who should be on lipid lowering therapy are, with no correlation to their genetic risk. We set out to see whether communicating personalized risk, including polygenic risk, for coronary artery disease would drive the adoption of lipid lowering therapy. (more…)
Author Interviews, Columbia, Genetic Research, Hematology, NEJM / 16.12.2021 Interview with: Markus Y Mapara, MD Professor of Medicine Director of the Blood and Marrow Transplantation Columbia University Medical Center What is the background for this study? What are the main findings?  Response: Sickle cell disease is caused by a point mutation in the beta-globin gene of hemoglobin  resulting in the production of abnormal hemoglobin which leads to formation of sickle-shaped RBC under conditions of low oxygen. Sickle cell disease affects about 100,000 patients in the US which are predominantly African  American. The only curative approach is to perform an allogeneic bone marrow transplant which is however fraught with significant treatment-related risks if a matched sibling donor is not available. The current study describes the successful application of a novel gene therapy  to treat patients with sickle cell disease. The strategy is based on a gene-addition approach to introduce the genetic information for a Hemoglobin F-like molecule termed HgAT87Q into hematopoietic stem cells. The expression of this novel  hemoglobin prevents polymerization of HgbS  and has now been demonstrated to prevent the occurrence of vaso-occlusive pain crises in sickle cell disease patients. (more…)
Author Interviews, Genetic Research, NEJM / 10.11.2021 Interview with: Professor Sir Mark Caulfield Professor of Clinical Pharmacology William Harvey Research Institute Queen Mary University of London What is the background for this study? Response: Rare diseases affect 6% of the population in western nations and there are approximately 10,000 different disorders and many remain without a genomic diagnosis after usual testing during their life time. In 2013 the UK Government launched the 100,000 Genomes Project and created Genomics England to investigate the role of whole genome sequencing in rare disease, cancer and infection. Whole genome sequencing gives the most comprehensive read out of the entire genome. To do this we partnered with the National Institute for Health Research (NIHR) BioResource and 9 hospitals across England1. Our New England Journal of Medicine paper published on the 11th November 2021 reports findings on the early rare disease participants who helped us pilot procedures and processes that would be used to enrol at scale across the NHS and revealed the potential benefits for rare disease1. (more…)
Author Interviews, Genetic Research, Ophthalmology / 08.06.2021 Interview with: Louis Pasquale, MD, FARVO Professor of Ophthalmology Icahn School of Medicine at Mount Sinai. Site Chair of the Department of Ophthalmology Mt. Sinai Hospital and Vice Chair of Translational Ophthalmology Research Mount Sinai Healthcare System What is the background for this study? Response: Studies on the relation between caffeine intake and glaucoma have been contradictory, although our work suggested an adverse association amongst people with a self-reported family history of glaucoma. (more…)
Author Interviews, Genetic Research, Parkinson's / 06.05.2021 Interview with: Clemens R. ScherzerClemens R. Scherzer, M.D. Center for Advanced Parkinson Research Harvard Medical School Brigham and Women’s Hospital Boston, MA What is the background for this study? Response: Parkinson's disease is the fastest growing brain disorder. The number of patients is projected to double to 14 million by 2040. The total cost of Parkinson's is $52 billion every year in the U.S. Yet, there are no medicines available to slow the disease. Current treatments temporarily alleviate symptoms, but do not address the underlying disease process, which continues to relentlessly progress. To begin to solve this puzzle, we searched the genome of 3,821 Parkinson's disease patients for genetic variants linked to rapid progression over time to dementia, which is a major determinant for a Parkinson's disease patient’s quality of life. These patients were deeply characterized in the International Genetics of Parkinson Disease Progression (IGPP) Consortium, a grass-roots, collaborative network of Parkinson’s investigators, with 31,578 longitudinal study visits over up to 12 years from disease onset.  (more…)
Author Interviews, Cancer Research, Gastrointestinal Disease, Genetic Research / 03.05.2021 Interview with: Judy H. Cho, MD, Dean of Translational Genetics Director of The Charles Bronfman Institute for Personalized Medicine Icahn School of Medicine at Mount Sinai What is the background for this study? Would you briefly describe Crohn's disease? Whom does it primarily affect? Response: Crohn’s disease is a chronic inflammatory intestinal disease, which affects ~3 million Americans a year. Its most typical age of onset ranges from 15-30 years, and many of those diagnosed also exhibit frequent abnormal healing and complications that constrict the digestive tract. The highest risk genetic mutations that increase risk for Crohn’s disease are found in the gene NOD2; these were first reported 20 years ago. Biological mechanisms by which NOD2 mutations drive Crohn’s disease, and especially fibrotic complications, have been incompletely described up until this point. Further, the reasons why many patients fail to respond to the commonly administered anti-TNF treatments also remain incompletely understood. (more…)
AACR, Author Interviews, Cancer Research, Genetic Research, NIH / 23.04.2021 Interview with: Nishanth Ulhas Nair, Ph.D. Affiliation: Staff Scientist at Cancer Data Science Laboratory, Center for Cancer Research National Cancer Institute (NCI), National Institutes of Health (NIH) Bethesda, Maryland, USA. Date: April 22, 2021 Dr. Raffit Hassan and Dr. Eytan Ruppin at the National Cancer Institute (NCI) are the senior authors of this study. What is the background for this study? Response: Malignant mesothelioma is an aggressive cancer with limited treatment options and poor prognosis. An in-depth knowledge of genetic, transcriptomic and immunogenic events involved in mesothelioma is critical for successful development of prognostics and therapeutic modalities. In this study we aim to address this by exploring a new large scale patient tumor dataset of 122 mesothelioma patients, called NCI mesothelioma patient data, along with their genomic, transcriptomic, and phenotypic information. Unlike previous large-scale studies which have been focused on malignant pleural mesothelioma patients, our dataset contains an approximately equal representation of malignant pleural and peritoneal mesothelioma patients which allows to identify any differences between them. (more…)
AACR, Baylor College of Medicine Houston, Cancer Research, Genetic Research, Prostate Cancer, Race/Ethnic Diversity, Social Issues / 10.04.2021 Interview with: Nicholas Mitsiades MD Associate Professor of Medicine - Hematology and Oncology Baylor College of Medicine Oncologist at the Dan L Duncan Comprehensive Cancer Center What is the background for this study? Response: African American men have higher risk of developing prostate cancer and up to 2.2-times higher mortality rate from prostate cancer relative to men of other ancestries. This is the largest health disparity across all cancers in the US. Socioeconomic factors, especially access to healthcare, definitely contribute to this disparity. African American men are diagnosed with prostate cancer at a more advanced stage than other races, and this is unfortunately very common at Ben Taub Hospital, our safety-net hospital in the Houston area, where we serve large racial and ethnic minority populations and patients who lack commercial insurance. (more…)
Author Interviews, Cost of Health Care, Genetic Research, Hematology, JAMA / 22.03.2021 Interview with: Patrick DeMartino MD Pediatric Hematology and Oncology Fellow Doernbecher Children's Hospital Oregon Health & Science University What is the background for this study? Response: Dozens of gene therapies are expected to be on the market within a decade or so. Much has been written about the high prices of the therapies currently on the market (exceeding $1 million). However, only a small number of patients are eligible for these existing therapies each year. Gene therapy for sickle cell disease (SCD) appears promising and would potentially apply to a relatively large number of individuals in the U.S. We sought to explore potential affordability challenges associated with a gene therapy for SCD. (more…)
Author Interviews, Genetic Research, Ophthalmology, Science / 12.03.2021 Interview with: eye-eyecolor-geneticsDr Pirro Hysi Senior Lecturer in Ophthalmology Kings College London What is the background for this study? Response: - Iris (eye) color is an important human trait. It is one of the main features that makes our faces unique and recognizable. Iris color is similar to other pigmentatio traits, like hair and skin color, in that it is determined by the concentration and relative ratios of the melanin pigment. Pigmentation traits are roughly determined by several of the same genes regulating pigmentation, but many other genes seem to selectively determine pigmentation in any of these tissues. (more…)
AHA Journals, Author Interviews, Genetic Research, Heart Disease / 08.03.2021 Interview with: Giordano Bottà, PhD CEO and Co-founder Allelica The Polygenic Risk Score Company What is the background for this study? Response: Previous research identified that polygenic risk score (PRS) has the highest predictive power compared to other risk factors and identifies individuals with the same risk of those with familial hypercholesterolemia, but are invisible to traditional risk assessment. We explored for the first time the interplay between the main causes of atherosclerosis, LDL cholesterol and PRS.  We were interested in helping cardiologists understand why some individuals have bad arteries full of plaques while others don't in presence of the same LDL levels and no additional risk factors. Our findings explain why this is the case: LDL does not affect everyone the same. We believe that we are at the forefront of a change of paradigm in cardiovascular risk assessment: LDL levels cannot be accessed without considering the genetics of an individual. (more…)
Author Interviews, Genetic Research / 03.02.2021 Interview with: Igor Chesnokov, Ph.D Department of Biochemistry and Molecular Genetics School of Medicine University of Alabama at Birmingham, Alabama What is the background for this study? Response: DNA replication is fundamentally important for tissue development, growth and homeostasis. Impairments of the DNA replication machinery can have catastrophic consequences for genome stability and cell division. Meier-Gorlin Syndrome (MGS) is an autosomal recessive disorder that is also known as ear, patella, short stature syndrome and/or microtia, absent patella, micrognathia syndrome, traits highlighting the core clinical phenotypes. The genes affected by MGS mutations include many members of pre-replicative complex (pre-RC), such as Origin Recognition Complex (ORC) subunits (Orc1, Orc4, Orc6), Cdc6, Cdt1, CDC45, MCM5 as well as Geminin, suggesting that the clinical phenotype is caused by defects in DNA replication initiation. As the pre-RC complex is essential for DNA replication, the mutations in its components are expected to impair cell proliferation and reduce growth. The smallest subunit of ORC, Orc6, is the most divergent and enigmatic among ORC subunits. Orc6 is important for DNA replication in all species. Metazoan Orc6 proteins consist of two functional domains: a larger N-terminal domain important for binding of DNA and a smaller C-terminal domain important for protein-protein interactions. A mutation coding for a tyrosine 232 to serine alteration (Y232S) in the C-terminal domain of Orc6 is linked to MGS in humans. Recently, a new Orc6 mutation was described that also resulted in MGS. Unlike the previously described MGS mutation, this amino acid substitution, Lysine 23 to Glutamic acid (K23E), localizes in the N-terminal domain of Orc6.  (more…)
Author Interviews, Breast Cancer, Genetic Research, JAMA, Race/Ethnic Diversity / 22.01.2021 Interview with: Kent Hoskins, MD Eileen Lindsay Heidrick Professor in Oncology Division of Hematology/Oncology University of Illinois at Chicago Director of Cancer Genetics Co-Leader, Breast Cancer Research Group University of Illinois Cancer Center What is the background for this study? Response: The racial disparity in breast cancer mortality emerged in the US in the late 1980s in the wake of widespread implementation of mammography screening and the development of successful systemic adjuvant therapies for early breast cancer. Unfortunately, more than three decades later, Black women in the US still have a 40% higher mortality rate from breast cancer compared with non-Hispanic White women despite similar disease incidence. Health disparities research has primarily focused on the fact that Black women have a higher incidence of the aggressive triple-negative subtype, and that they are more likely to present with more advanced stages of disease. As important as those factors are, in recent years our group and others reported that Black women with hormone receptor-positive breast cancer have worse survival than non-Hispanic white women even after adjustment for stage at diagnosis and treatment. Since nearly 2/3 of breast cancers in Black women are hormone receptor-positive, this is a significant contributor to the overall mortality disparity. Importantly, these studies also suggested that Black women disproportionately develop biologically aggressive forms of hormone-dependent breast cancer, which is typically considered a more favorable disease subtype. Using data on more than 70,000 patients from the SEER registry that is linked to data from Genomic Health Laboratory, which provides the Oncotype DX recurrence score (the most commonly ordered prognostic/predictive multi-gene expression assay for early breast cancer), we set out to address three questions: 1) is there evidence of disproportionately aggressive tumor biology among Black women with hormone receptor (HR)-positive breast cancer, as reflected in the Oncotype DX recurrence score? 2) Is there a racial survival disparity even among patients with early stage, axillary node-negative tumors with comparable recurrence scores on the Oncotype assay? and 3) Is there is a difference in the prognostic accuracy of the Oncotype assay between Black and non-Hispanic white patients, since there was limited representation of Black women in the development and validation of the Oncotype assay and other prognostic/predictive assays?  (more…)
Author Interviews, Autism, Fertility, Genetic Research / 12.01.2021 Interview with: Michael Skinner,  PhD Eastlick Distinguished Professor Founding Director, Center for Reproductive Biology School of Biological Sciences Washington State University Pullman WA What is the background for this study? Response: Over twenty years ago we identified the existence of a non-genetic form of inheritance through analysis of environmentally induced epigenetic transgenerational inheritance of disease, now well established in a number of species including humans.  I was giving a talk on this topic at a meeting in Spain.   This study was initiated following the scientific meeting in Spain with an in vitro fertilization clinical group that said they had access to sperm from males with and without autistic children.  It took several years to collect and characterize the samples, and find financial support for the study.  Once this was done then we did the molecular analysis to see if the sperm from fathers with autistic children had epigenetic, DNA methylation alterations, that associated with them having offspring with autism. (more…)
Author Interviews, COVID -19 Coronavirus, Genetic Research, NYU / 19.12.2020 Interview with: John T. Poirier, PhD Assistant Professor of Medicine, NYU Grossman School of Medicine Director, Preclinical Therapeutics Program Perlmutter Cancer Center An NCI-designated Comprehensive Cancer Center NYU Langone Health Smilow Research Center New York, NY 10016 What is the background for this study? Response: The goal of this study was to identify in as much detail as possible the genes that SARS-CoV-2, the virus that causes COVID-19, needs to successfully infect a human host cell. CRISPR technology played a key role in this research; it was used to disrupt every gene in the human genome in parallel and study which ones were required for infection. (more…)
Author Interviews, Genetic Research, Orthopedics / 18.12.2020 Interview with: Karin Magnusson PT, PhD Associate Researcher Lund University and Norwegian Institute of Public Health What is the background for this study? Response: Anterior cruciate ligament (ACL) injury is one of the most common knee injuries, for which very limited data has been presented on the genetic contribution. Based on our knowledge of the role of genetics in the development of ACL-rupture related traits, such as joint hypermobility and knee osteoarthritis, we hypothesized that heritability might play a role also in ACL injury. Using the Swedish Twin Registry, which is the world's largest twin registry and in this study including more than 88.000 twins, we had unique data to for the first time reliably estimate the heritability for this common knee injury.  (more…)
Alzheimer's - Dementia, Author Interviews, Cognitive Issues, Genetic Research, Nutrition / 11.12.2020 Interview with: Auriel Willette, PhD Assistant Professor Food Science and Human Nutrition Iowa State University What is the background for this study? Response: To date, pharmacology therapies done to slow down or halt Alzheimer's disease have been inconclusive. Lifestyle interventions like changes in diet and activity are also mixed but do show some promise. Dietary clinical trials or self-reported diet have tended to focus on groups of foods such as the Mediterranean or MIND diet. To build from this excellent work, we were curious if we could pinpoint specific foods that were correlated with changes in fluid intelligence over time. Fluid intelligence represents our ability to creatively use existing knowledge, working memory, and other components of "thinking flexibly." Further, we tested if these patterns of association differed based on genetic risk. In this case, genetic risk was defined as having a family history of Alzheimer's disease or having 1-2 "bad" copies of the Apolipoprotein E (APOE) gene, which is the strongest genetic risk factor for Alzheimer's disease. (more…)
Author Interviews, Genetic Research, Hematology / 08.12.2020 Interview with: Steven Pipe, MD Professor of Pediatrics and Pathology Laurence A. Boxer Research Professor of Pediatrics and Communicable Diseases Pediatric Medical Director, Hemophilia and Coagulation Disorders Program Director, Special Coagulation Laboratory University of Michigan What is the background for this study? Response: Hemophilia B is an inherited bleeding disorder where patients are missing clotting factor IX (9), a critical blood clotting protein.  Patients with a severe deficiency are at risk for traumatic and spontaneous bleeds – primarily into joints.  Repeated bleeding into joints causes more than acute pain and swelling but also leads to inflammatory and degenerative changes in joints that eventually leads to severe debilitating arthritis that can be crippling.  To try to prevent this, patients as young as infants are placed on regular infusions of clotting factor IX concentrates.  The relatively short half-life of factor IX means patients must infuse on average once to twice a week.  These can only be delivered intravenously – parents and then patients themselves have to learn this.  Prophylaxis must be continued lifelong to try to prevent bleeding events and protect joint health over the lifespan.  This is a tremendous burden on the patient and their caregivers. Even with regular prophylaxis, joint bleeds may still occur and arthropathy may still ensue.  This is because the blood levels often reach critically low levels prior to the next infusion.  Gene therapy aims to deliver a functional copy of the factor IX gene such that the patient’s own liver will make a continuous supply of factor IX that is delivered to the bloodstream.  At steady state with levels close to or within the normal range, patients would no longer be subject to bleeding events and would not require prophylaxis any longer.  We hope that such a one-time treatment would produced durable, “functionally curative” levels of factor IX. (more…)
Author Interviews, Cancer Research, Genetic Research / 01.12.2020 Interview with: Nina Bhardwaj MD PhD Director of Immunotherapy Tisch Cancer Institute Icahn School of Medicine at Mt Sinai Ward-Coleman Chair in Cancer Research Professor of Hematology and Oncology What is the background for this study? Response: Neoantigens are novel antigens expressed by tumors as a result of somatic mutations or frame shift mutations. They can be very immunogenic and consequently they are being incorporated into cancer vaccine platforms. In most cases it is necessary to determine each patient’s individual mutations and customize their vaccine antigens accordingly. We sought to identify shared mutations in cancer antigens which are deficient in DNA repair mechanisms namely microsatellite unstable tumors. These tumors have mutations in genes that normally are responsible for ensuring that DNA is properly replicated. Because these genes encode proteins that ensure proper repair around micro-satellite areas (which contain short repeated sequences of DNA and are present in similar regions from one person’s genome to the next), when they are mutated, these regions may not be repaired. Consequently due to nucleotide deletions and insertions one gets frame shift mutations which result in new protein expression which can be shared across tumors, as has been observed for a few regions. We therefore did a comprehensive study of a subset of tumors to determine the breadth of shared frame shift mutations. (more…)
Author Interviews, Brigham & Women's - Harvard, Cancer Research, Genetic Research, Melanoma, Prostate Cancer / 23.11.2020 Interview with: Saud H AlDubayan, M.D. Instructor in Medicine, Harvard Medical School Attending Physician, Division of Genetics, Brigham and Women's Hospital Computational Biologist, Department of Medical Oncology, Dana-Farber Cancer Institute Associate Scientist, The Broad Institute of MIT and Harvard What is the background for this study? What are the main findings? Response: The overall goal of this study was to assess the performance of the standard method currently used to detect germline (inhered) genetic variants in cancer patients and whether we could use recent advances in machine learning techniques to further improve the detection rate of clinically relevant genetic alterations. To investigate this possibility, we performed a head to head comparison between the current gold-standard method for germline analysis that has been universally used in clinical and research laboratories and a new deep learning analysis approach using germline genetic data of thousands of patients with prostate cancer or melanoma. This analysis showed that across all different gene sets that were tested, the deep learning-based framework was able to identify additional cancer patients with clinically relevant germline variants that went undetected by the standard method. For example, several patients in our study also had germline variants that are associated with an increased risk of ovarian cancer, for which the surgical removal of the ovaries (at a certain age) is highly recommended. However, these genetic alterations were only identified by the proposed deep learning framework.     (more…)
Aging, Author Interviews, Genetic Research, McGill / 22.11.2020 Interview with: Richard C. Austin, PhD Professor and Career Investigator of the Heart and Stroke Foundation of Ontario Amgen Canada Research Chair in Nephrology McMaster University and St. Joseph’s Healthcare Hamilton, Ontario, Canada What is the background for this study? What are the main findings? Response: A previous study published in 2011 by my collaborator, Dr. Michel Chretien at the IRCM, identified a rare mutation in the PCSK9, termed Q152H. Individuals harboring this mutation demonstrated dramatic reductions in their LDL cholesterol levels and had a significantly lower risk of CVD. Furthermore, individuals harboring the Q152H mutation showed increases in longevity with no evidence of other diseases such as liver disease, cancer and chronic kidney disease. This Q152H mutation was unique with only 4 families in Quebec shown to harbor this genetic variant. In terms of its effect on PCSK9 expression/activity, the mutation at Q152H was precisely at the cleavage site in PCSK9 necessary for its activation. As a result, the Q152H mutation fails to be cleaved and activated, thereby blocking its secretion into the circulation. This is why the Q152H mutation is considered a loss-of-function PCSK9 mutant. Given our lab's interest in endoplasmic reticulum (ER) stress and ER storage diseases, we began to collaborate with Drs. Chretien and Seidah at the IRCM to investigate whether this Q152H mutant, when overexpressed in liver cells, would cause ER stress and liver cell injury. This was based on the findings that the Q152H mutant does not undergo autocatalytic cleavage and its subsequent secretion from liver cells. It is well known in the literature that the accumulation of misfolded or inactive proteins in the ER gives rise to ER stress and cell injury/dysfunction. As a result, we initially showed to our surprise that overexpression of the Q152H mutant in liver cells failed to cause ER stress BUT increased the protein levels of several important ER chaperones, GRP78 and GRP94, known to PROTECT against liver cell injury/dysfunction. As part of our JCI study, we furthered these studies to examine the effect of the Q152H mutant when overexpressed in the livers of mice. This is where we demonstrated that the Q152H mutation showed protection against ER stress-induced liver injury/dysfunction. (more…)
Author Interviews, Dermatology, Genetic Research / 20.11.2020 Interview with: Jillian F. Rork, MD Assistant Professor of Dermatology Dartmouth-Hitchcock Medical Center at Manchester and The Geisel School of Medicine Society for Pediatric Dermatology Member What is the background for this study? Would you briefly explain the genetic condition of Down syndrome? Response:  Down syndrome is the most common chromosomal abnormality, occurring in approximately 1 in 700 newborns in the United States.  Trisomy of chromosome 21 can result in multisystem involvement such as hearing loss, heart defects, autoimmune conditions and dementia. This study focuses on how trisomy 21 affects one of the body’s largest organs, the skin. Current literature addressing dermatologic conditions associated with Down syndrome is limited. There is often emphasis on rare skin conditions such as elastosis perforans serpiginosa, milia-like idiopathic calcinosis cutis, and eruptive syringomas. There is lack of consensus on incidence of more common disorders. We performed a retrospective chart review of 101 patients with Down syndrome in our dermatology practice at the University of Massachusetts to better describe associated skin conditions. (more…)
Author Interviews, Dermatology, Genetic Research, Melanoma / 19.11.2020 Interview with: Sarah I. Estrada, M.D., FCAP  Laboratory Director Affiliated Dermatology® What is the background for this study? What are the main findings? Response: As a dermatopathologist who makes diagnoses on lesions that may be melanoma, I’m faced with the reality that my accurate interpretation of biopsy tissue is key for the patient to be treated most effectively. Often histopathological evaluation is straightforward but not as often as I would like. The study presented here offers a new test that can be used in conjunction with my evaluation to determine if a questionable lesion is in fact melanoma. The test was developed to take into account the gene expression of the lesion which may factor in characteristics that I cannot visually observe. The test was validated and has shown very promising accuracy metrics. (more…)