Author Interviews, Colon Cancer, Genetic Research, Journal Clinical Oncology / 03.11.2015

MedicalResearch.com Interview with: Hans F.A. Vasen, MD Department of Gastroenterology Leiden University Medical Center and Netherlands Foundation for the Detection of Hereditary Tumours Leiden, the Netherlands Medical Research: What is the background for this study? Dr. Vasen: People with familial colorectal cancer (CRC) have a 3-6 fold increased risk of colorectal cancer. It has been estimated that about 2% of the population have familial CRC (about 2.7 million people in the US). Previous studies showed that colonoscopic surveillance reduces the CRC-mortality by >80%. In people with hereditary CRC, i.e., Lynch syndrome (10 fold increased risk of CRC), an intensive screening program with colonoscopy 1x/1-2 years, is recommended. In familialcolorectal cancer, the optimal screening program  is unknown. Medical Research: What are the main findings? Dr. Vasen: In this randomized trial with 528 individuals at risk for familial CRC, we compared screening intervals of 3 and 6 years. We found that patients had significant more high-risk adenomas (precursor lesions of CRC) at 6-years-follow-up compared to at 3-years-follow-up. However, because of the relatively low rate of high-risk adenomas at 6 years (7%) and the absence of colorectal cancer in the 6-years group, we consider a 6-year-interval safe. (more…)
Author Interviews, Genetic Research, Kidney Disease, Nature, Stem Cells / 24.10.2015

MedicalResearch.com Interview with: Benjamin Freedman, Ph.D. Assistant Professor | University of Washington Department of Medicine | Division of Nephrology Member, Kidney Research Institute Member, Institute for Stem Cell and Regenerative Medicine Seattle WA 98109  Medical Research: What is the background for this study? What are the main findings? Dr. Freedman: We are born with a limited number of kidney tubular subunits called nephrons. There are many different types of kidney disease that affect different parts of the nephron. The common denominator between all of these diseases is the irreversible loss of nephrons, which causes chronic kidney disease in 730 million patients worldwide, and end stage renal disease in 2.5 million. Few treatments have been discovered that specifically treat kidney disease, and the therapeutic gold standards, dialysis and transplant, are of limited availability and efficacy. Pluripotent stem cells are a renewable source of patient-specific human tissues for regeneration and disease analysis. In our study, we investigated the potential of pluripotent cells to re-create functional kidney tissue and disease in the lab. Pluripotent cells treated with a simple chemical cocktail matured into mini-kidney 'organoids' that closely resembled nephrons. Using an advanced gene editing technique called CRISPR, we created stem cells with genetic mutations linked to two common kidney diseases, polycystic kidney disease (PKD) and glomerulonephritis. Mini-kidneys derived from these genetically engineered cells showed specific 'symptoms' of these two different diseases in the petri dish. (more…)
Author Interviews, Endocrinology, Genetic Research, Weight Research / 22.10.2015

Urszula T. Iwaniec, Ph.D. Associate Professor Skeletal Biology Laboratory School of Biological and Population Health Sciences Oregon State University Corvallis, OR 97331MedicalResearch.com Interview with: Urszula T. Iwaniec, Ph.D. Associate Professor Skeletal Biology Laboratory School of Biological and Population Health Sciences Oregon State University Corvallis, OR 97331 Medical Research: What is the background for this study? What are the main findings? Dr. Iwaniec: Excessive weight gain in adults is associated with a variety of negative health outcomes. Unfortunately, dieting, exercise, and pharmacological interventions have had limited long-term success in weight control and can result in detrimental side effects, including accelerating age-related bone loss.  Leptin, a hormone produced by fat cells plays an essential role in weight regulation. Delivery of leptin directly into the hypothalamus by gene therapy normalizes body weight. We investigated the efficacy of using hypothalamic leptin gene therapy as an alternative method for reducing weight in skeletally-mature female rats and determined the impact of leptin-induced weight loss on bone. Our findings show that hypothalamic leptin gene therapy reduced body weight with minimal effects on bone mass or microarchitecture. (more…)
Author Interviews, Genetic Research, Lancet, Macular Degeneration, Ophthalmology / 12.10.2015

Professor P. Elizabeth Rakoczy Centre for Ophthalmology and Visual Sciences The University of Western Australia Head of Department - Molecular Ophthalmology Lions Eye Institute AustraliaMedicalResearch.com Interview with: Professor  P. Elizabeth Rakoczy Centre for Ophthalmology and Visual Sciences The University of Western Australia Head of Department - Molecular Ophthalmology Lions Eye Institute Australia Medical Research: What is the background for this study? Prof. Rakoczy: Wet age related macular (wet-AMD) is the major cause of blindness in the developed world. It is treated with frequent anti-VEGF injections into the eye. Our preclinical studies demonstrated that following the subretinal injection of a recombinant adeno-associated vector (rAAV) carrying a natural inhibitor of neovascularization (sFlt-1), leaky new, abnormal vessels can be controlled and retinal anatomy improved. The rAAV.sFlt-1 based Ocular Biofactory™ platform has potentially significant advantages over existing technologies as it is designed to provide sustained production of a naturally occurring antiangiogenic agent, sFlt-1, in situ in the eye. In this trial we investigated the safety of rAAV.sFlt-1 in patients diagnosed with wet-AMD. (more…)
Author Interviews, Cancer Research, Genetic Research / 10.10.2015

Huma Q. Rana, MD Clinical Director, Cancer Genetics and Prevention Dana-Farber Cancer Institute in BostonMedicalResearch.com Interview with: Huma Q. Rana, MD Clinical Director, Cancer Genetics and Prevention Dana-Farber Cancer Institute in Boston Medical Research: What is the background for this study? What are the main findings? Dr. Rana: -        Li-Fraumeni syndrome (LFS) is thought to be a rare, inherited condition that  causes high lifetime risks for multiple cancers.  It is caused by mutations in the TP53 gene.  Traditionally, only people with striking personal or family histories of cancer underwent genetic testing for TP53 mutations, as there are well-established testing criteria.   This gene was usually tested for in isolation, meaning not combined with testing of other genes.  Due to technological advances, namely multi-gene panels (MGP), many more people are having their TP53gene analyzed.    This included a patient of mine who somewhat surprisingly  tested positive for a TP53 mutation.    This led us to investigate whether people who test positive for TP53 mutations on MGPs are different from ones who test positive on traditional or single-gene (SG) testing. We compared individuals tested for TP53 single gene versus multigene panel testing to determine if there were differences in the percent of mutation carriers meeting current testing criteria for LFS.   Our data showed that 73% of individuals sent in for single gene testing of TP53 met Classic or Chompret (2009) criteria for LFS, whereas only 30% of those sent in for multi-gene panel testing met criteria (p=0.0000001).  When we looked at the most up-to-date testing criteria, which includes Classic, Chompret, or a personal diagnosis of early-onset breast cancer (age at ≤35), 85% of individuals in the single gene group who were positive met criteria, while only 53% of the mutation carriers identified on a multi-gene panel did.   These data suggest that multi-gene panel testing enables us to identify TP53 mutation carriers who may not have otherwise been identified if testing were limited to those who meet established LFS criteria. (more…)
Author Interviews, Fertility, Genetic Research / 09.10.2015

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

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

Jacqueline Alvarez-Leite MD, Ph.D Full Professor, UFMG Moore Laboratory Massachusetts General HospitalMedicalResearch.com Interview with: Jacqueline Alvarez-Leite  MD, Ph.D Federal University of Minas Gerias in Brazil Medical Research: What is the background for this study? What are the main findings? Dr. Alvarez-Leite : Obesity is now a global epidemic and bariatric surgery is now the main therapeutic option for those individuals with extreme obesity in which clinical treatments failed. However, a significant proportion of those patients regain the weight lost 3-4 years after surgery. Therefore, some metabolic or genetic trait may be related to weight regain. The rs9939609 single nucleotide polymorphism (SNP) in the fat mass and obesity- associated (FTO) gene is one of the most studied genes involved in obesity. However, few studies have been conducted on patients who underwent bariatric surgery. In our study, we evaluated the influence of  this FTO SNP on body weight and composition, and weight regain in 146 patients during a 60-mo follow-up period after bariatric surgery. We observed that there was a different evolution of weight loss in individual with obesity carriers of the FTO gene variant after bariatric surgery. However, this pattern is evident at only 2 y post bariatric
 surgery, inducing a lower proportion of surgery success (percentage of excess weight loss >50%) and greater and earlier weight regain after 3-y of follow-up. Multiple regression 
analyses showed that the variation in rs9939609 was a significant and independent predictor for regaining weight during the 
5-y follow-up period. (more…)
Author Interviews, Genetic Research, Ophthalmology / 05.10.2015

MedicalResearch.com Interview with: Dr. Annabel Christ PhD Max-Delbrueck-Center for Molecular Medicine Berlin, Germany Medical Research: What is the background for this study? Dr. Christ: The development and function of the retina in all vertebrate species follow the same principles. Still, there is one important feature that distinguishes the mammalian eye from that of others inasmuch as it does not grow much after birth. In contrast, in fish or reptiles, the retina continuously grows, even in adults. The mechanism that restricts the growth of the mammalian eye remains enigmatic. Yet, understanding this mechanism may offer therapeutic strategies to block eye growth in cases of severe nearsightedness or to induce growth of the retina in patients with retina degeneration. To explore the mechanisms that control human eye growth we studied a genetic form of extreme eye overgrowth (buphthalmia). It is caused by an inherited defect in the gene encoding LRP2, a receptor in the retina. We reasoned that this exceptional form of eye disease might tell us something about the concepts governing eye growth in all humans. (more…)
Author Interviews, Cancer Research, Colon Cancer, Genetic Research, JNCI, Mayo Clinic, Race/Ethnic Diversity / 05.10.2015

Harry H. Yoon, MD Mayo Clinic Rochester, MN 55905MedicalResearch.com Interview with: Harry H. Yoon, MD Mayo Clinic Rochester, MN 55905 Medical Research: What is the background for this study? What are the main findings? Dr. Yoon: In the U.S., the survival of patients with colon cancer is known to differ by race, with individuals of black race having worse outcomes than those of white race. However, it has been difficult to tease apart why the differences in survival exist. It is generally believed that social or other non-biologic factors (eg, decreased access to care, suboptimal treatment) contribute to the discrepancy.  It’s also known that differences in the general medical condition of patients could affect how long a patient lives. However, it is unknown whether there are race-based differences in the biology of colon tumors themselves.  This biology can be reflected in the genetic composition of tumors, as well as by whether and how quickly the cancer returns after the patient has undergone surgery and chemotherapy. In addition, it is unknown whether race-based differences in biology may be related to the age of the patient at the time of diagnosis.  Blacks with colorectal cancer typically have an earlier age of onset than whites do. A major barrier to addressing these questions are that there are very few large populations of colon cancer patients where everyone had the same disease stage and received uniform treatment, and where patients were monitored for years afterward specifically to see whether the cancer returned.  It is much harder to measure whether cancer has returned (ie, cancer recurrence), as compared to simply knowing whether a patient is alive or dead.  This difference is important, because knowing about cancer recurrence sheds more light on cancer biology than only knowing about patient survival, since many factors unrelated to cancer biology (eg., heart disease) can affect whether a person is alive or dead. The most reliable data on cancer recurrence (not just patient survival) generally comes from patients who have enrolled in a clinical trial.  In the Alliance N0147 trial, all patients had the same cancer stage (ie, stage III), underwent surgery and received standard of care chemotherapy (ie, “FOLFOX”) after surgery.  Patients had uniform, periodic monitoring after chemotherapy to see if the cancer returned. In other words, examining racial outcomes in this cohort largely eliminates some of the key factors (eg, decreased access to care, suboptimal treatment) that are believed to contribute to racial discrepancies, and provides a unique opportunity to determine if differences in cancer biology between races may exist. This study was done to see if colon cancers are genetically different based on race, and whether race-based differences exist in cancer recurrence rates. The study found that tumors from whites, blacks, and Asians were different in terms of the frequency of mutations in two key cancer-related genes, BRAF and KRAS.  Tumors from whites were twice as likely to have mutated BRAF (14% in whites compared to 6% in Asians and 6% in blacks).  Tumors from blacks had the highest frequency of KRAS mutations (44% in blacks compared to 28% in Asians and 35% in whites).  Tumors from Asians were the mostly likely to have normal copies of both genes (67% in Asians compared to 50% in blacks and 51% in whites). Next, the study found that the colon cancers among blacks had more than double the risk of cancer recurrence, compared to whites.  However, this discrepancy was only evident among young patients (ie, aged less than 50 years).  Almost 50% of younger black patients experienced colon cancer recurrence within 5 years, compared to ~30% of black patients over age 50, or compared to white or Asian patients regardless of age. The worse outcome among young blacks remained evident even after adjusting for many potential confounding factors, such as tumor grade, the number of malignant nodes, or the presence of BRAF or KRASmutations.  Because this question was examined in a clinical trial cohort of uniform stage and treatment, the role of multiple important potential confounders was diminished. To our knowledge, this is the first report indicating that colon cancers from young black individuals have a higher chance of relapsing after surgery and chemotherapy, compared to those from white individuals. (more…)
Author Interviews, Depression, Genetic Research, JAMA / 03.10.2015

Dr. David Brent MD Department of Psychiatry Western Psychiatric Institute and Clinic University of Pittsburgh Medical Center Pittsburgh, PennsylvaniaMedicalResearch.com Interview with: Dr. David Brent MD Department of Psychiatry Western Psychiatric Institute and Clinic University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Medical Research: What is the background for this study? Dr. Brent: Youth with a parent with a history of depression are at increased risk for having a depressive episode themselves. Medical Research: What are the main findings? Dr. Brent: Those who received a cognitive behavioral educational group program were less likely to have had a depressive episode, and were functioning better than those who did to receive the program 6 years later, especially if their parent was NOT depressed at the time that they received the program. If the parent was depressed then the program was no better than usual care. (more…)
Author Interviews, Breast Cancer, Chemotherapy, Genetic Research, NEJM / 29.09.2015

Dr. Kathy D. Miller, MD Indiana University Melvin and Bren Simon Cancer CenterMedicalResearch.com Interview with: Dr. Kathy D. Miller, MD Indiana University Melvin and Bren Simon Cancer Center Medical Research: What is the background for this study? What are the main findings? Dr. Miller: Previous studies had found a small but real benefit with the addition of chemotherapy to anti-estrogen treatment in patients with hormone sensitive disease. The challenge for patients and clinicians has always been that the benefit of chemotherapy is quite small and the toxicity can be substantial. The Oncotype Dx recurrence score assay was developed to identify patients who could safely be treated with anti-estrogen therapy alone (and conversely those who truly need and would derive a much larger benefit from chemotherapy). When the Oncotype Dx RS was applied to samples stored from a previous randomized trial, patients with low risk scores didn't seem to benefit from chemotherapy. While those initial results had some impact on treatment, many were concerned about eliminating chemotherapy on the basis of one small retrospective trial. The overall trial enrolled 10,253 women. 1626 (15.9%) had a Recurrence Score of 0-10 and were assigned to receive antiestrogen therapy alone without chemotherapy. After five years 99.3% (98.7, 99.6%) for were free of distant relapse (that is to say, 99.3% of women had NOT had recurrence of breast cancer at distant sites in the body). Overall survival was 98%. (more…)
Author Interviews, Breast Cancer, Brigham & Women's - Harvard, Genetic Research, Journal Clinical Oncology, Race/Ethnic Diversity / 20.09.2015

Aditya Bardia MBBS, MPH Attending Physician, Massachusetts General Hospital Cancer Center, Assistant Professor, Harvard Medical School Boston, MA 02114MedicalResearch.com Interview with: Aditya Bardia MBBS, MPH Attending Physician, Massachusetts General Hospital Cancer Center, Assistant Professor, Harvard Medical School Boston, MA 02114   Medical Research: What is the background for this study? What are the main findings? Response:  Multiple studies have consistently shown that African American women with cancer, including breast cancer, have worse outcomes than Caucasian counterparts. While socioeconomic issues, including access to care plays an important role, the contribution of tumor biology has been less clear. In this study, utilizing exome sequencing data, we linked the racial distribution of primary breast cancer with tumor genotypic traits, including somatic mutations, gene-expression profiles and intra-tumor heterogeneity. We observed that in addition to having a higher prevalence of triple negative breast cancer than Caucasian women (something that has been documented in the literature), African American women had a significantly higher prevalence of TP53 mutations, TNBC basal-like 1 and mesenchymal stem-like tumors, and intratumor genetic heterogeneity, and all of which suggest more aggressive tumor biology, suggesting that differences in tumor genomic profile contribute, at least partly, to the known racial disparity in survival between African Americans and Caucasians breast cancer patients. (more…)
Author Interviews, Cancer Research, Case Western, Colon Cancer, Genetic Research / 16.09.2015

Ahmad M. Khalil, PhD Department of Genetics School of Medicine Case Western Reserve University Cleveland, Ohio 44106-4955 MedicalResearch.com Interview with: Ahmad M. Khalil, PhD Department of Genetics School of Medicine Case Western Reserve University Cleveland, Ohio 44106-4955 Medical Research: What is the background for this study? What are the main findings? Dr. Khalil: DNA in human cells is modified chemically by methylation. The process of DNA methylation plays important roles in protecting human DNA and ensures proper gene expression.  In cancer cells, the process of DNA methylation becomes deregulated, however, the mechanisms of how this occurs are not known.  In our study, we have uncovered a novel mechanism on how colon cancer cells change their DNA methylation, and consequently, become more tumorigenic. We specifically identified a long non-coding RNA that interacts with and regulates the enzyme that modifies DNA with methylation - the enzyme is called DNMT1. This lncRNA become suppressed in colon tumors, which we believe is a key step in loss of DNA methylation in colon cancer cells. (more…)
Author Interviews, Dermatology, Genetic Research / 12.09.2015

Thomas N. Darling, MD, PhD Department of Dermatology Uniformed Services University of the Health Sciences Bethesda, MD 20814 MedicalResearch.com Interview with: Thomas N. Darling, MD, PhD Department of Dermatology Uniformed Services University of the Health Sciences Bethesda, MD 20814 Medical Research: What is the background for this study? What are the main findings? Dr. Darling: Many people with tuberous sclerosis complex (TSC) have skin tumors that can bleed or cause distress. Only surgical approaches were useful for treating these skin tumors in the past. Recently, drugs called mTOR inhibitors, including sirolimus, were shown to shrink internal tumors in those affected by tuberous sclerosis complex. We wanted to document what happens to the skin tumors in those being treated with oral sirolimus. We found that most patients taking oral sirolimus showed improvement in their skin tumors, and that these effects were maintained during a couple years of treatment. We did not observe any evidence for the skin tumors becoming resistant to the drug. (more…)
Author Interviews, Genetic Research, Sexual Health / 12.09.2015

MedicalResearch.com Interview with: Binbin Wang, PhD Center for Genetics, National Research Institute for Family Planning Beijing China Medical Research: What is the background for this study? What are the main findings? Dr.Wang:Homosexuality has become an important issue all around the world, as well as in China. Beside of the human right problems it poses, the reality that more and more HIV cases are infected through homosexual activity,especially men who have sex with men (MSM), should be concerned. People are wondering how homosexuality develops. As a genetic researcher, I'd like to find the answers in the field of genetics. This study is based on previous evidence that genes may have impact on homosexuality. Besides, animal models have provided clues that abnormality in some neurotransmitters, such as dopamine, may alter the sex behavior of animals. Therefore, we choose COMT (the gene catechol-O-methyltransferase) as the target, which is important for the synthesis of dopamine. We find that an amino acid residue change in COMT could increase the risk of developing male homosexuality. Our results provide some evidence that male homosexuality is connected with genes. (more…)
Aging, Author Interviews, Genetic Research, Smoking, UCLA / 11.09.2015

Dr. Morgan Elyse Levine PhD Postdoctoral Fellow Department of Human Genetics University of California, Los Angeles MedicalResearch.com Interview with: Dr. Morgan Elyse Levine PhD Postdoctoral Fellow Department of Human Genetics University of California, Los Angeles Medical Research: What is the background for this study? What are the main findings? Dr. Levine: Studies using mice, worms, and flies have suggested that longevity may be linked to stress resistance. All of us are constantly encountering things that damage our cells and tissue and disrupt physiological functioning. Therefore, people who are genetically predisposed to better prevent or repair this damage may age slower. Smoking is one of the most damaging things someone can do to their health, yet some smokers are able to survive to extreme ages. This study looked at long-lived smokers to see if we could identify a "genetic signature". We generated a genetic risk score that was found to be associated with longevity both in smokers and non-smokers, and also appeared to be associated with cancer risk. (more…)
Author Interviews, Breast Cancer, Genetic Research, UCSF / 04.09.2015

Dr. Elisa Long PhD Assistant professor UCLA Anderson School of ManagementMedicalResearch.com Interview with: Dr. Elisa Long PhD Assistant professor UCLA Anderson School of Management Medical Research: What is the background for this study? What are the main findings? Dr. Long: The study was motivated by my own diagnosis of triple-negative breast cancer last year, at the age of 33. I also learned that I carried a BRCA1 mutation, despite no family history. As a patient, I would have benefitted tremendously from a universal BRCA screening program, but as a health services researcher, I had to ask if indiscriminate screening of all women in the U.S.—where only 1 in 400 carry a mutation—is a good use of resources. Using a previously published decision analytic model, we calculated the cost-effectiveness of universal BRCA screening. We find that compared to screening based on family history, it is not cost-effective, assuming a test price of $2,000 to $4,000. However, as the price of genetic testing continues to fall, as indicated by the $249 test now offered by Color Genomics, universal BRCA screening becomes much more affordable. Additionally, population screening of Ashkenazi Jewish women—among whom 1 in 50 carry a BRCA mutation—is very cost-effective, because the chances of finding a carrier are much higher. (more…)
Author Interviews, Chemotherapy, Genetic Research, Melanoma / 04.09.2015

Rutao Cui M. D., Ph. D.  Vice Chair, Professor,  Department of Pharmacology and Experimental Therapeutic Associate Professor of Pharmacology and Dermatology, and Member The Cancer Center Director The Laboratory of Skin Cancer Therapeutics (LSCT) Boston UniversityMedicalResearch.com Interview with: Rutao Cui M. D., Ph. D.  Vice Chair, Professor Department of Pharmacology and Experimental Therapeutic Associate Professor of Pharmacology and Dermatology, and Member The Cancer Center Director The Laboratory of Skin Cancer Therapeutics (LSCT) Boston University Medical Research: What is the background for this study? What are the main findings? Dr. Cui: Recent studies have revealed that the APC/CCdh1 E3 ubiquitin ligase may function as a tumor suppressor. However, the tumor suppressor role of APC/CCdh1 in melanoma remains largely unclear. Here, we report sporadic mutations occurring in APC components, including Cdh1 in human melanoma samples and that loss of APC/CCdh1 may predispose human melanomagenesis. (more…)
Author Interviews, Genetic Research, Pediatrics, Psychological Science / 02.09.2015

Beate W. Hygen PhD Student Department of Psychology Norwegian University of Science and Technology Social ScienceMedicalResearch.com Interview with: Beate W. Hygen PhD Student Department of Psychology Norwegian University of Science and Technology Social Science Medical Research: What is the background for this study? Response: The study is part of the Trondheim Early Secure Study (TESS) conducted at the  Department of Psychology, Norwegian University of Science and Technology (NTNU) and NTNU Social Science. The main aim of TESS is to detect risk and protective factors with regards to children’s mental health and well-being.  TESS examines multiple factors which may play a role in children`s development. There is substantial research, based on diathesis-stress theorizing, indicating that some individuals, including children, are more susceptible to the negative effects of contextual adversity than are others. However, according to differential susceptibility theory, such "vulnerable" individuals may also be the ones that benefit the most from positive environmental conditions. Thus, some individuals are more malleable for "better and for worse" to environmental exposures. The article Child exposure to serious life events, COMT, and aggression: Testing differential susceptibility theory was designed to examine if the COMT polymorphism moderated the effect of early-life adversity on aggressive behavior. Thus, we sought to competitively evaluate which model of person X environment interaction best accounted for the anticipated differential effects of life event stress on children's aggressive behavior. (more…)
Author Interviews, Cancer Research, Genetic Research / 02.09.2015

Sameek Roychowdhury, MD, PhD Assistant Professor, Internal Medicine, College of Medicine Assistant Professor, Department of Pharmacology, College of Pharmacy Department of Internal Medicine Division of Medical Oncology Wexner Medical Center The Ohio State UniversityMedicalResearch.com Interview with: Sameek Roychowdhury, MD, PhD Assistant Professor, Internal Medicine, College of Medicine Assistant Professor, Department of Pharmacology College of Pharmacy Department of Internal Medicine Division of Medical Oncology Wexner Medical Center The Ohio State University Medical Research: What is the background for this study? What are the main findings? Dr. Roychowdhury: Precision cancer medicine is a new paradigm to match patients to therapies based on the molecular alterations in their cancer. Novel genomic testing of cancer using next generation sequencing can reveal numerous mutations for each patient across many genes and types of cancer, and this requires detailed time-intensive interpretation. Driver mutations can confer a selective growth or survival advantage to cancer cells, while passenger mutations do not. Cancer Driver Log, or CanDL, is meant to aid interpretation of mutations by providing the latest literature evidence for individual driver mutations, and thereby aiding pathologists, lab directors, and oncologists in interpreting mutations found in their patient’s cancer. (more…)
Author Interviews, Brain Cancer - Brain Tumors, Genetic Research / 02.09.2015

Roger Packer MD Senior Vice President Center for Neuroscience & Behavioral Health Children's National Medical Center Washington, D.C. Medicalresearch.com Interview with: Roger Packer MD Senior Vice President Center for Neuroscience & Behavioral Health Children's National Medical Center Washington, D.C.   MedicalResearch: What is the background for this study? What are the main findings? Dr. Packer: The background is that medulloblastoma is the most common childhood malignant brain tumor. It carries with it a variable prognosis. For some subsets of patients, with current available treatment which includes surgery, radiation and chemotherapy, we see survival rates as high as 90% (and often cures) 5 years following diagnosis and treatment. However, for some subsets of patients, survival rates are much poorer, in those with higher risk characteristics as low as 40% at 5 years. Current treatment also carries with it a significant risk for long term sequelae, including intellectual loss secondary to radiation therapy and persistent, at times devastating neurologic complications such as unsteadiness. To try to improve our understanding and ultimately our therapy for medulloblastoma, an international working group has shared patient specimens and patient information to attempt to determine what the molecular predictors of outcome are for children with medulloblastoma and if such molecular genetic findings can be used to develop better, safer therapies. Children’s National is part of this international collective of institutions, which published this and other studies. The main findings of this study are that complex, integrated genetic analysis of tumor specimens can be used to better understand and set the scene for better treatment of medulloblastoma.  Medulloblastoma can be broken into relatively distinct, molecular subtypes each with its own prognosis and potential therapy. A major finding of this study was that within a given tumor, different areas showed the same molecular genetic pattern. The importance of this is that since the tumors are relatively the same in different areas, molecularly-targeted therapies have an excellent chance of working on the entire tumor, resulting in better tumor control and safer treatments. (more…)
Author Interviews, Case Western, Dermatology, Genetic Research / 27.08.2015

Nely Aldrich, MD Department of Dermatology University Hospitals Case Medical CenterMedicalResearch.com Interview with: Nely Aldrich, MD Department of Dermatology University Hospitals Case Medical Center Medical Research: What is the background for this study? What are the main findings? Dr. Aldrich:   To our knowledge, no formal studies have been performed on the genetic vs. environmental factors that lead to the development of rosacea. Our department has the unique opportunity to attend the Twins Days festival in Twinsburg, Ohio. This is a yearly festival where thousands of twin pairs come from all over the world. This was the perfect setting to ask our research question. Our main finding was that there is an approximately 50% contribution of genetics to rosacea and the other 50% can be attributed to environmental factors. Sun exposure, smoking, alcohol use, skin cancer history, and heart disease were also found to be correlated with a higher rosacea severity. (more…)
Author Interviews, Breast Cancer, Duke, Genetic Research, JAMA / 27.08.2015

Michaela Ann Dinan Ph.D. Assistant Professor in Medicine Member of Duke Cancer Institute Duke University School of MedicinMedicalResearch.com Interview with: Michaela Ann Dinan Ph.D. Assistant Professor in Medicine Member of Duke Cancer Institute Duke University School of Medicine Medical Research: What is the background for this study? What are the main findings? Dr. Dinan: For many years we have known that overall, women with early stage, hormone receptor positive breast cancer show an overall survival benefit from the receipt of adjuvant chemotherapy.  However, depending on the age of the patient, we have also known that between 3 to 10% of patients appear to be truly experiencing this survival benefit and that we are treating a lot of women unnecessarily.  The use of the Oncotype DX assay has provided additional information for patients to assess who at low risk of disease progression and can forgo chemotherapy. In this study we looked to see whether the adoption of this assay was associated with reduce rates of chemotherapy in women over the age of 65.  We found that somewhat surprisingly, there was no overall association with receipt of the assay and use of chemotherapy.  However, in women who had high risk disease, receipt of the assay was associated with reduced rates of chemotherapy use.  In patients with low risk disease, receipt of the assay was associated with increased chemotherapy use. (more…)
Author Interviews, Breast Cancer, Genetic Research, Race/Ethnic Diversity / 26.08.2015

Tuya Pal MD Division of Population Sciences Department of Health Outcomes and Behavior Moffitt Cancer Center Tampa, Florida MedicalResearch.com Interview with: Tuya Pal MD Division of Population Sciences Department of Health Outcomes and Behavior Moffitt Cancer Center Tampa, Florida   Medical Research: What is the background for this study? Dr. Pal:  Young Black women bear a disproportionate burden associated with breast cancer incidence and mortality compared to their White counterparts. Given that inherited mutations in the BRCA1 and BRCA2 genes are more common among young breast cancer survivors, we questioned to what extent mutations in these genes might contribute to the racial disparity in breast cancer incidence among young women. Medical Research: What are the main findings? Dr. Pal:  Through conducting the largest U.S. based study of BRCA mutation frequency in young black women diagnosed with breast cancer at or below age 50, we discovered they have a much higher BRCA mutation frequency than that previously reported among young white women with breast cancer.  Specifically, of the 396 Black women with breast cancer diagnosed at or below age 50, 12.4% had mutations in either BRCA1 or BRCA2.  Furthermore, over 40 percent of those with a mutation had no close relatives with breast or ovarian cancer, which suggests that family history alone may not identify those at risk for carrying a BRCA mutation.  (more…)
Author Interviews, Genetic Research / 21.08.2015

Hendrik Marks Ph.D Group leader Epigenetics of Stem Cells Radboud University, Department of Molecular Biology, RIMLS, Nijmegen, The Netherlands MedicalResearch.com Interview with: Hendrik Marks Ph.D Group leader Epigenetics of Stem Cells Radboud University, Department of Molecular Biology, RIMLS Nijmegen, The Netherlands   Medical Research: What is the background for this study? What are the main findings? Dr. Marks: In mammals, sex is determined by two so-called "sex" chromosome: males have a single X chromosome as well as a Y chromosome, whereas females have two copies of the X chromosome. However, if both X chromosomes were to be active in female cells, these cells would have a double dosis of X-chromosomal gene products as compared to male cells. As this is lethal for almost all cells, female cells shut off one X chromosome in every cell in a process called X inactivation. This process occurs during early embryonic development. A lot is known about how this process is turned on, but is was unclear how such a silencing process spreads along a full chromosome. In order to further study this, we used female mouse embryonic stem cells (mESCs) as a model system and initiated X inactivation by means of differentiation. With the latest technologies, we were able to keep the two X chromosomes apart and measure one of them – with its 166 million base pairs (Mbs) – in detail. Every day we checked which parts of the chromosome had been switched off. The whole process took about eight days, and the inactivation spreads out from the centre of the X chromosome towards the ends. That doesn’t happen gradually but moves jumpwise from domain to domain. Domains are long pieces of DNA (of around 1Mb) that cluster together in knots. As it seems that X inactivation jumps from domain to domain, we now know that these domains are co-regulated. Also, we collected strong evidence that the same process is occurring in human. (more…)
Author Interviews, Education, Genetic Research, Social Issues / 21.08.2015

Ben Domingue Assistant Professor (starting 9/2015) Stanford Graduate School of Education   MedicalResearch.com Interview with: Ben Domingue Assistant Professor (starting 9/2015) Stanford Graduate School of Education     Medical Research: What is the background for this study? What are the main findings? Response: Earlier research has started to illuminate which genetic variants are associated with educational attainment. Subsequent work has taken these variants, combined them into a "polygenic score", and studied how that polygenic score predicts educational attainment. Our research continues this line of inquiry by examining the predictive performance of that polygenic score in a representative sample of US adults who are now in their 30s. A few notable findings include that: (A) the polygenic score predicts educational attainment in the African Americans in our sample and (B) that the polygenic score is associated with neighborhood characteristics. As with earlier research, we are able to show that the higher score sibling from within a family will complete more years of schooling (on average) than their lower score co-sib. (more…)
Author Interviews, Brigham & Women's - Harvard, Genetic Research, Heart Disease, Nature / 18.08.2015

Susan A. Slaugenhaupt PhD Professor of Neurology, Harvard Medical School Associate Geneticist, Department of Neurology, Molecular Neurogenetics Unit Center for Human Genetic Research Massachusetts General HospitalMedicalResearch.com Interview with: Susan A. Slaugenhaupt PhD Professor of Neurology, Harvard Medical School Associate Geneticist, Department of Neurology, Molecular Neurogenetics Unit Center for Human Genetic Research Massachusetts General Hospital   Medical Research: What is the background for this study? What are the main findings? Dr. Slaugenhaupt: Mitral valve prolapse (MVP) is one of the most common human diseases affecting 1 out of every 40 people worldwide.  The mitral valve is found between two chambers of the heart, and mitral valve prolapse results when the valve does not close properly.  By studying families in which multiple members have mitral valve prolapse, we have identified a biological explanation for the disease.  Mutations in the DCHS1 gene cause mitral valve prolapse in three families, and suggest that early defects in heart valve formation during development contribute to the progressive deterioration of the valve. (more…)
Author Interviews, Breast Cancer, Genetic Research, JAMA, Ovarian Cancer / 13.08.2015

Leif W. Ellisen, M.D., Ph.D Professor of Medicine, Harvard Medical School Program Director, Breast Medical Oncology Co-Leader, Breast Cancer Program MGH Research Scholar MGH Cancer Center  Boston, MA 02114MedicalResearch.com Interview with: Leif W. Ellisen, M.D., Ph.D Professor of Medicine, Harvard Medical School Program Director, Breast Medical Oncology Co-Leader, Breast Cancer Program MGH Research Scholar MGH Cancer Center Boston, MA 02114 Medical Research: What is the background for this study? What are the main findings? Dr. Ellisen: The traditional approach to genetic testing for women with suspected hereditary breast and/or ovarian cancer risk is to test for BRCA1 and BRCA2 alone. Recent studies have shown that testing with a multi-gene panel finds relevant risk gene mutations in substantially more women than does testing for BRCA1 and BRCA2 alone. However, one of the concerns about broader multi-gene testing has been that the results really wouldn’t change what you told women about their risk and management – either because the risk associated with the other genes may not be as high as for BRCA1/2, or because the clinical practice guidelines associated with some of the other genes are less specific. Our study sought to determine how often testing such women using a multi-gene panel would find mutations in genes other than BRCA1/2, and more importantly to ask whether finding those mutations would change how you would manage the patient and their family. We found that multi-gene panel testing finds relevant risk gene mutations in substantially more women (approximately 40% more) than does testing for BRCA1 and BRCA2 alone. Furthermore, in a case-by-case analysis we showed that finding mutations in these other genes is likely to change the clinical management that is considered or recommended for the majority of the mutation-positive women and their families.  Notably, our analysis of the predicted management change is based not just on the gene mutation alone, but on how the gene appears to be behaving in that particular family. (more…)
Author Interviews, Genetic Research, Prostate Cancer / 09.08.2015

Dr Helen Ross-Adams Cancer Research UK, LondonMedicalResearch.com Interview with: Dr Helen Ross-Adams Cancer Research UK, London Medical Research: What is the background for this study? What are the main findings? Dr. Ross-Adams: Prostate cancer is the most common non-skin cancer in men in both the UK and US. At the moment, prostate cancer is diagnosed and monitored mainly on the basis of blood tests for prostate specific antigen (PSA), a protein in the blood. MRI scans and examination of biopsy tissue samples under a microscope are also used to decide on the best course of action for each patient. Despite all this, as a community, we still struggle to reliably predict which men with an initial diagnosis of prostate cancer will go on to have a fast-growing, aggressive form of the disease (a ‘tiger’) from men who will have a much slower-growing form of the disease that won’t really cause problems in the man’s lifetime (a ‘pussycat’). This means some men may get treatment they don’t need, while others could benefit from earlier, more intensive treatment. With this in mind, we studied a total of 250 men with prostate cancer and tested their tumour and healthy tissues at the molecular level. The idea was two-fold:
  • Could we identify different sub-types of prostate cancer using this genetic information, and
  • Could we link any of the sub-types we did find with other patient characteristics that clinicians would normally have, like histological staging information or PSA test results?
We looked at their DNA, to see whether any regions were deleted or repeated (copy number alterations), and we also measured the activity levels of thousands of genes in the tumour and healthy prostate tissues (gene expression). Each of these approaches on their own can be used to stratify patients, but we decided to combine this information and hopefully find genes that had a big impact on prostate cancer. Using this approach, we identified five different subtypes of prostate cancer, each with their own ‘molecular profile’:
  • One group had lots of DNA deletions and only low levels of certain genes
  • Another had lots of repeated DNA with high levels of associated genes
  • Two more groups had very ‘quiet’ genomes, with very few changes at the DNA level, and not much disruption at the gene expression level
  • The fifth and final group had an intermediate amount of copy number changes (DNA level), but no major changes at the gene expression level (mRNA level)
When we correlated these different molecular subtypes with the patients’ standard post-surgery follow-up data (the results of 6-monthly PSA tests), we found that these subtypes predicted how well a patient would do after surgery. We ultimately identified 100 key genes (a gene signature) that were most useful in classifying men into one of the 5 cancer subtypes we identified. This was derived from 150 men in Cambridge, UK. To check our findings, we repeated the same work in a group of 100 men from Stockholm, Sweden who had also had prostate surgery, and found that the 100 gene signature worked just as well – it subdivided the men into 5 different groups, each with different rates of relapse. In both cases, men with the most genetic alterations had the greatest chance of relapsing after surgery.   (more…)