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 55905 MedicalResearch.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, Pennsylvania MedicalResearch.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 Center MedicalResearch.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 02114 MedicalResearch.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 Management MedicalResearch.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 University MedicalResearch.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 Science MedicalResearch.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 University MedicalResearch.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 Center MedicalResearch.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 Medicin MedicalResearch.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 Hospital MedicalResearch.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 02114 MedicalResearch.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, London MedicalResearch.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…)
Author Interviews, Genetic Research, NYU, PLoS / 08.08.2015

Dr. Arthur Caplan Ph.D. Drs. William F and Virginia Connolly Mitty Professor Head of the Division of Medical Ethics New York University, Langone Medical Center, NY MedicalResearch.com Interview with: Dr. Arthur Caplan Ph.D. Drs. William F and Virginia Connolly Mitty Professor Head of the Division of Medical Ethics New York University, Langone Medical Center, NY Medical Research: What is the background of the Down Syndrome Prenatal Education Act? Dr. Caplan: For many years women who receive a positive prenatal test for Down syndrome have been aborting their pregnancies. Rates of pregnancy termination, while somewhat disputed, are very high. In the USA, UK and Denmark they have consistently been over 80% for many years. This has led some parents of children with Down to wonder if the counseling that women receive is biased negatively against a life with Down. They working with pro life legislators in many states have promoted legislation to insure that mothers carrying an infant with a diagnosis of Down Syndrome have access to positive information and helpful resources about life with a child with Down. This legislation has been enacted in many states and there is a Federal law as well. Medical Research: How does Chloe's Law impact genetic testing? Dr. Caplan: These laws represent a seismic shift in counseling about genetic disorders and diseases. Historically counselors aspired to be value-free—simply trying to provide objective information to their patients/clients. With laws like Chloe’s the public is saying they do not trust the neutrality of counselors and counseling and want more positive messages sent about Down. This is quite simply an ethical revolution in how counseling for Down will be done in the future. It is also a direct Challenge to the legitimacy of value-neutrality as a counseling norm that certainly will be extended to other conditions and disabilities where abortion rates are high and where there is the belief that there is unjustified prejudice or bias against disabilities among those working in clinical genetics. (more…)
Author Interviews, Cancer Research, Genetic Research / 02.08.2015

Christos Nikolaidis Ph.D. Laboratory of Pharmacology Medical School, Democritus University of Thrace Dragana, Alexandroupolis Greece MedicalResearch.com Interview with: Christos Nikolaidis Ph.D. Laboratory of Pharmacology Medical School, Democritus University of Thrace Dragana, Alexandroupolis Greece Medical Research: What is the background for this study? Response: Epigenetic changes are part of the natural history of cervical neoplasia. Tracking these changes at the molecular level is necessary for understanding disease progression, response to treatment and prognosis. Epigenetic biomarkers can potentially assess the stage of cervical intraepithelial neoplasia (CIN). This information can be used for screening purposes, to improve the overall quality of cervical cancer diagnostics. Medical Research: What are the main findings? Response: Paired boxed 1 (PAX1) gene methylation status has been widely used as a biomarker for cervical cancer screening. We have conducted a meta-analysis of the diagnostic test accuracy of PAX1 methylation, on moderate cervical dysplasia or worse (CIN2+) versus normal epithelium, and severe cervical dysplasia or worse (CIN3+) versus normal epithelium, for a total population of 1385 women. The results of this assay were generally satisfactory for CIN2+ vs normal, and extremely satisfactory for CIN3+ vs normal (Sensitivity=0.77, Specificity=0.92, AUC=0.931). This raises the possibility of utilizing this biomarker to improve current diagnostic protocols. (more…)
Author Interviews, Genetic Research / 01.08.2015

Dr. Rosalind Arden Centre for Philosophy of Natural & Social Science London School of Economics London MedicalResearch.com Interview with: Dr. Rosalind Arden Centre for Philosophy of Natural & Social Science London School of Economics London MedicalResearch: What is the background for this study? What are the main findings? Dr. Arden: We've known for a while that people who score higher on IQ-type tests tend to live longer. A study published in the British Medical Journal (Whalley & Deary, 2001) examined intelligence in childhood and later survival. People born in Scotland in 1921 took an IQ-type test at age 11 in 1932. Those with higher test scores were more likely to survive to age 76. What we haven't known is 'why?' One possibility is that advantages from being raised in a wealthier family may enhance intelligence and health - leading to brighter people living longer. Another possibility is that many genes that influence brains also influence bodies. If well-built brains co-occur with well-built bodies, that could also explain the link. These are only two of several possible explanations. We aimed to test whether genes caused the link between intelligence and life-expectancy. We found 1) the link between intelligence and life expectancy is positive but small. 2) The cause of the link is almost all genetic. We found this by examining differences within twin pairs. Twins offer a quasi-natural experiment because they share many features of the environment that are often thought (mistakenly) to cause differences between people. And marvelously, for science there are two kinds of twins, with known genetic relatedness (100 % or 50%). This give us a means to test questions about the cause of differences in a population, as well as the causes of correlations among traits within a population. (more…)
Author Interviews, Genetic Research, Heart Disease, PNAS, Rheumatology / 27.07.2015

MedicalResearch.com Interview with: Philippe Bouillet, PhD Walter and Eliza Hall Institute Parkville, Vic Australia Medical Research: What is the background for this study? What are the main findings? Dr. Bouillet: This study was initiated when we discovered mice that developed rheumatoid arthritis as a result of what was obviously a spontaneous dominant genetic mutation. Using several approaches, we identified the mutation as the insertion of a mobile genetic element called retrotransposon into the regulatory sequences of the gene encoding tumor necrosis factor (TNF). The mutation caused excessive amounts of TNF to be produced, a known cause of rheumatoid arthritis. The surprise came when some mice with the mutation died prematurely and suddenly with from heart disease. We showed that excess TNF also led to inflammation of the aortic and mitral valves, causing aortic regurgitation. Depending on the genetic background of the mice, the disease could also culminate in aortic aneurysm and death. We also investigated the regulatory region of the TNF gene and identified novel regulators and a new genetic element that normally make sure that levels of serum TNF are kept within reasonable limits, high enough to ensure its numerous physiological functions, low enough to prevent its harmful effects such as those described here. (more…)
Author Interviews, Cancer Research, Genetic Research, MD Anderson / 24.07.2015

Eduardo Vilar-Sanchez, MD, PhD Assistant Professor, Department of Clinical Cancer Prevention Division of OVP, Cancer Prevention and Population Science The University of Texas MD Anderson Cancer Center Houston, TX 77030 MedicalResearch.com Interview with: Eduardo Vilar-Sanchez, MD, PhD Assistant Professor, Department of Clinical Cancer Prevention Division of OVP, Cancer Prevention and Population Science The University of Texas MD Anderson Cancer Center Houston, TX 77030 Medical Research: What is the background for this study? What are the main findings? Dr. Vilar-Sanchez: I am a physician scientist at The University of Texas MD Anderson Cancer Center (MDA), a medical oncologist specializing in cancer genetics, especially colorectal cancer (CRC) syndromes. At MD Anderson, I have medical practice consisting primarily of colorectal cancer, as part of the clinical cancer arm of MD Anderson. I became interested in this topic because it is now well recognized that colorectal cancer is increasing in prevalence in young individuals. CRC is the third most common cancer in the US with 90% diagnosed in patients older than 50. While most CRC patients develop cancer in their 60s or 70s, the incidence is now rising in individuals younger than 50. Over the next two decades, it is projected that the incidence of CRC in young adults under 35 will double. Only 5% of all CRC patients have a known hereditary predisposition cancer syndrome. Patients diagnosed at or under age 35 represent an extreme phenotypic presentation, constituting only 1.5% of all CRC cases. We retrospectively reviewed all patients with CRC patients age 35 or under, who were evaluated by the Genetic Services group at MD Anderson. In this group, a surprising 30% had a recognized hereditary cancer syndrome, a marked increase compared to the general CRC population. (more…)
Author Interviews, Genetic Research, Heart Disease / 24.07.2015

MedicalResearch.com Interview with: Dr. Paraskevi Christofidou Department of Cardiovascular Sciences, University of Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Leicester UK MedicalResearch: What is the background for this study? Dr. Christofidou: Homozygosity arises when identical alleles are present on both chromosomes. Runs of homozygosity (ROHs) are very long segments of uninterrupted sequences of homozygous variants across the human genome. Runs of homozygosity represent "re-union" of pieces from DNA from parents in their children. The two DNA copies are identical because have been inherited from a common ancestor somewhere in the distant past. Runs of homozygosity are recognized signature of recessive inheritance, because they allow unmasking of recessive variants. Recessive variants only show their effect when present on both chromosomes of an individual's genome. Some of these ROHs may potentially harbor variants that exert their pathological effects in the homozygous recessive state. This is important because it helps us better understand the consequences of the recessive model of inheritance in relation to complex diseases. Coronary artery disease (CAD) is a terminal clinical manifestation of cardiovascular disease and is the leading cause of death worldwide and is the UK's single biggest killer. Nearly one in six men and one in ten women die from CAD. Coronary artery disease is a complex, multifactorial disorder originating from a complicated interplay of multiple genetic and environmental factors. Contributions of ROHs to the genetic architecture of CAD are not known. The primary goal of this project was a comprehensive analysis of association between genome-wide homozygosity measures and CAD in individuals of white European ancestry. A secondary aim was to explore the association of ROHs and gene expression in human monocytes and macrophages. MedicalResearch: What are the main findings? Dr. Christofidou: Our analysis of 24,320 individuals from 11 populations of white European ethnicity revealed statistically significant differences in homozygosity levels between individuals with Coronary artery disease and control subjects. On average, individuals with CAD had 0.63 ROHs more than control subjects. The average total length of ROHs was approximately 1046.92 kb greater in individuals with CAD than control subjects. We were able to qualify a measure of genome-wide homozygosity levels in relation to CAD - an estimated 13% increase in CAD per 1 standard deviation increase in the proportion of the autosomal genome covered by ROHs. Individual ROHs showed significant associations with monocyte and macrophage expression of genes located nearby. These associations suggest that many ROHs might be signatures of biologically active recessive variants with a potential to regulate transcription. (more…)
Author Interviews, Connective Tissue Disease, Genetic Research, Rheumatology / 20.07.2015

MedicalResearch.com Interview with: Dr. Changfu Kuo MD PhD Division of Rheumatology, Orthopaedics, and Dermatology School of Medicine, University of Nottingham, Nottingham, England Division of Rheumatology, Allergy, and Immunology Chang Gung Memorial Hospital, Taoyuan, Taiwan Medical Research: What is the background for this study? What are the main findings? Dr. Kuo: Systemic lupus erythematosus (SLE) is a prototype of autoimmune disease with features like autoantibody production and multiple target organ damage. SLE can affect any part of the body and the course of the disease is highly diverse and unpredictable. SLE can occur at any age and affect both females and males with a sex ratio of 9 to 1. Familial predisposition has been recognised as a risk factor previously and heritability of SLE has been estimated to be 66%. However, previous reports are often based on less robust sampling strategies and case ascertainment which generally depend on hospital records, self-reported diagnosis and disease registries, therefore limiting generalisability. The previous estimates of heritability are overestimated, due to a lack of consideration of shared environmental contribution. This study utilised a unique health insurance database that provides information on the whole population of Taiwan and permits determination of spouse and first-degree relatives. Over 23 million people were included in this study. Furthermore, through inclusion of SLE status of the spouse in our analyses the study is also able to examine how much of familial clustering results from genetic versus shared environmental factors. Overall the familial relative risk is 16.92. The genetic contribution to SLE susceptibility is estimated to be 44%. In addition to SLE, other autoimmune diseases are also more prevalent in individuals with a family history of SLE. (more…)
Author Interviews, Genetic Research, Heart Disease, McGill / 20.07.2015

Christopher Labos MD CM, MSc FRCPC Division of Epidemiology, Biostatistics and Occupational Health McGill University Montreal, Quebec Canada MedicalResearch.com Interview with: Christopher Labos MD CM, MSc FRCPC Division 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: There have been great advances in the field of genetics in recent years. Especially in cardiology, a number of genetic variants have been identified that are associated with cardiovascular disease. But it is not clear how useful these variants are in terms of predicting future evens in patients that have already suffered a myocardial infarction. What we found in our study is that a genetic risk score composed of the 30 most common genetic variants associated with cardiovascular diseases was not useful in predicting recurrent events in the first year after a patient suffered a myocardial infarction. (more…)