Genomic Testing Can Improve Confidence in Prostate Cancer Treatment Strategy

MedicalResearch.com Interview with:

Dr. John L. Gore, MD Associate Professor Adjunct Associate Professor-Surgery Department of Urology University of Washington

Dr. John Gore

Dr. John L. Gore, MD
Associate Professor
Adjunct Associate Professor-Surgery
Department of Urology
University of Washington

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The rationale for our study derives from the uncertainty that both patients and clinicians confront when trying to make decisions about adjuvant therapy for prostate cancers found to have aggressive pathologic features at the time of radical prostatectomy. There is level 1 evidence in support of adjuvant radiation therapy in this setting, but several factors restrain providers from recommending adjuvant radiation. We found that interjecting a genomic test that predicts the risk of clinical metastases 5 years after surgery impacts the treatment recommended and helps men and clinicians feel more confident in the decision they are making or recommending.

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21-Gene Expression Assay May Clarify Need For Chemotherapy in Early Breast Cancer

MedicalResearch.com Interview with:

Carlos H. Barcenas M.D., M.Sc. Assistant Professor Department of Breast Medical Oncology MD Anderson Cancer Center

Dr. Carlos Barcenas

Carlos H. Barcenas M.D., M.Sc.
Assistant Professor
Department of Breast Medical Oncology
MD Anderson Cancer Center

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Over the last decade we have realized that we were over-treating many early stage breast cancer patients. In addition to the chemotherapy’s obvious side effects, there are also long term complications for breast cancer survivors. Since 2005, we are using a 21-gene-expression assay that predicts the risk of distant recurrence among early stage breast cancer patients. In 2015, initial results from the international clinical trial, TAILORx, found that women with hormone receptor positive, HER2 and lymph node negative early stage disease that had a low recurrence score (RS) of 0-10 from this assay could have chemotherapy omitted altogether. While these findings changed care for women with a low RS, questions remain regarding the management of women with an intermediate RS, defined by this trial as a RS of 11-25. For our retrospective, single-institution study we identified 1,424 stage I and II breast cancer patients with hormone receptor positive, HER2 and lymph node negative treated between 2005 and 2011 who underwent the 21-gene expression assay. The RS distribution was: 297 (21 percent) scored 0–10; 894 (63 percent) scored 11-25; and 233 (16 percent) scored >25.

Of those groups, 1.7, 15 and 73.4 percent received chemotherapy, respectively. With a median follow up of 58 months, those with a RS of 11-25 had an invasive disease-free survival (IDFS) rate at five years of 92.6 percent, regardless if patients received chemotherapy or not. Among those patients who did not receive chemotherapy, the estimated rates of IDFS and overall survival was 93 percent and 98 percent, respectively, which was comparable to those who did receive chemotherapy.

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Mammaprint Profiling Improves Breast Cancer Adjuvant Treatment Decisions

MedicalResearch.com Interview with:

Dr. med. Rachel Würstlein</strong> Senior Specialist Clinic and Polyclinic for Obstetrics and Gynecology Klinikum der Ludwig-Maximilians-Universität München • Campus Innenstadt Munich

Dr. Rachel Wuerstlein

Dr. med. Rachel Würstlein
Senior Specialist
Clinic and Polyclinic for Obstetrics and Gynecology
Klinikum der Ludwig-Maximilians-Universität München • Campus Innenstadt
Munich

MedicalResearch.com: What is the background for this study?

Response: Gene expression profiles provide important information on the risk of recurrence, and subtyping in HR+ HER2- early breast cancer, in addition to conventional clinicopathological factors. The PRIMe study was performed by the West German Study Group (WSG) and prospectively investigated the impact of the gene expression tests MammaPrint, a 70-Gene Breast Cancer Recurrence Assay, and the corresponding 80-Gene Molecular Subtyping Assay, BluePrint, on adjuvant chemotherapy decisions for early-stage breast cancer patients.

To do this, a risk assessment (chemotherapy followed by endocrine therapy, versus endocrine therapy alone) for distant metastasis was performed in 452 patients from 27 study centers using conventional clinicopathological factors such as tumour size and grade first, then compared to the results of the gene expression tests MammaPrint and BluePrint. Doctors and patients then reviewed the results and made a decision on the optimal treatment plan, namely in deciding whether or not patients would benefit from, and should therefore be treated with adjuvant chemotherapy.

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Genetically Predisposed Patients May Develop ALS At Earlier Age

MedicalResearch.com Interview with:
Prof. Dr. Christine Van Broeckhoven PhD DSc
Professor in Molecular Biology and GeneticsUniversity of Antwerp
Science Director, VIB Center for Molecular Neurology
Research Director, Laboratory for Neurogenetics, Institute Born-Bunge
Senior Group Leader, Neurodegenerative Brain Diseases
University of Antwerp and
Dr. Sara Van Mossevelde, MD
Center for Molecular Neurology, VIB
Institute Born-Bunge, University of Antwerp
Department of Neurology and Memory Clinic
Hospital Network Antwerp Middelheim and Hoge Beuken
Antwerp, Belgium

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Patients with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) and a C9orf72 repeat expansion present with highly variable onset ages of disease. In the Belgian patient cohort the onset ages ranged from 29 to 82 years of age. This high variability suggested the influence of modifying factors on disease expression. As in other repeat expansion diseases, repeat length is the prime candidate as genetic modifier. In a molecular study (Gijselinck et al., Molecular psychiatry 2016), we were able to provide evidence for an inverse correlation of repeat length with onset age in affected parent – affected children in a C0orf72 families. Also, the degree of methylation of the C9orf72 repeat correlated with repeat size.

In this clinical study of affected parent – affected children pairs we provided additional evidence for the occurrence of disease anticipation in C9orf72 pedigrees by analyzing age at onset, disease duration and age at death in successive generations. Within 36 C9orf72 pedigrees with available age data of patients in two to four generations, we observed a significant decrease in age at onset across successive generation while no generational effect was seen on disease burden, disease duration or age at death.

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Gene Therapy Restores Hearing Down To A Whisper, in Mice

MedicalResearch.com Interview with:

Gwenaelle Geleoc, PhD Assistant Professor Department of Otolaryngology F.M. Kirby Neurobiology Center Children's Hospital and Harvard Medical School Boston, MA

Dr. Gwenaelle Geleoc

Gwenaelle Geleoc, PhD
Assistant Professor
Department of Otolaryngology
F.M. Kirby Neurobiology Center
Children’s Hospital and Harvard Medical School
Boston, MA

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: We seek to develop gene therapy to restore auditory and balance function in a mouse model of Usher syndrome. Usher syndrome is a rare genetic disorder which causes deafness, progressive blindness and in some cases balance deficits. We used a novel viral vector developed by Luk Vandenberghe and package gene sequences encoding for Ush1c and applied it to young mice suffering from Usher syndrome. These mice mimic a mutation found in patients of Acadian descent. We assessed recovery of hearing and balance function in young adult mice which had received the treatment. Otherwise deaf and dizzy, we found that the treated mice had recovered hearing down to soft sounds equivalent to a whisper and normal balance function.

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A1C May Be Less Accurate Measure of Diabetes in African Americans with Common Sickle Cell Trait

MedicalResearch.com Interview with:
Mary E. Lacy, MPH

Department of Epidemiology
Brown University School of Public Health
Providence, RI

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Hemoglobin A1c (A1C) is a blood test that is used to screen for and monitor diabetes. It measures average blood sugar control over the past 2-3 months.

A person with sickle cell trait is a carrier for sickle cell disease but often doesn’t have any clinical symptoms. African Americans are more likely than Whites to have diabetes and are more likely to have sickle cell trait. In this article we examined if A1C can be interpreted in the same way in people with and without sickle cell trait.

We found that, despite similar results on other measures of blood sugar control, people with sickle cell trait had lower A1C results than people without sickle cell trait. This means that A1C may underestimate diabetes risk in people with sickle cell trait.
We also found that, when using standard A1C cutoffs to screen for disease prevalence, we identified 40% fewer cases of prediabetes and 48% fewer cases of diabetes in individuals with sickle cell trait than in those without sickle cell trait. To me, this finding really underscores the potential clinical impact that the observed underestimation of A1C in those with sickle cell trait could have.

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Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer

MedicalResearch.com Interview with:
Matthew B Yurgelun, M.D

Instructor in Medicine, Harvard Medical School
Dana-Farber Cancer Institute

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: It has long been known that hereditary factors play a key role in colorectal cancer risk. It is currently well-established that approximately 3% of all colorectal cancers arise in the setting of Lynch syndrome, a relatively common inherited syndrome that markedly increases one’s lifetime risk of colorectal cancer, as well as cancers of the uterus, ovaries, stomach, small intestine, urinary tract, pancreas, and other malignancies. Current standard-of-care in the field is to test all colorectal cancer specimens for mismatch repair deficiency, which is a very reliable means of screening for Lynch syndrome. The prevalence of other hereditary syndromes among patients with colorectal cancer has not been known, though other such factors have been presumed to be quite rare.

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Over 100 Genetic Signals Influence Blood Pressure

MedicalResearch.com Interview with:

Helen R Warren PhD</strong> Analysis, Statistics, Genetic Epidemiology Queen Mary, University of London

Dr. Helen Warren

Helen R Warren PhD
Analysis, Statistics, Genetic Epidemiology
Queen Mary, University of London

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: This study analysed data from UK Biobank, which is a large cohort including over 500,000 male and female participants from across the UK, aged 40-69 years. We performed a genetic association study for blood pressure, which analysed ~140,000 individuals of European ancestry (as currently interim genetic data is only available for ~150,000 participants).

Our study identified 107 genetic regions associated with blood pressure, which had not been previously reported at the time of our analysis. All our new findings were robustly validated within independent replication data resources, comprising a large, total sample size of up to 420,000 individuals.

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Key Gene Linked To Brain Plasticity and Learning Identified

MedicalResearch.com Interview with:

Keerthi Krishnan PhD</strong> Cold Spring Harbor Laboratory Cold Spring Harbor, New York 11724,

Dr. Keerthi Krishnan

Keerthi Krishnan PhD
Cold Spring Harbor Laboratory
Cold Spring Harbor, New York 11724

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Rett Syndrome is diagnosed as a neurodevelopmental disorder in girls, caused mainly by mutations in the gene MECP2. Many previous studies, including mine, have shown that mutations in MECP2 result in improper communication between nerve cells in the brain during sensitive periods of development. However, it was unclear if the same mechanisms were responsible for cognitive and behavioral problems found in adulthood.

In this paper, we have utilized a natural, learned response called pup retrieval behavior to study adult neural plasticity in a female mouse model of Rett Syndrome. With some learning, adult female mice will gather scattered pups to the nest, in response to distress calls from the pups. We found that the Rett Syndrome model mice with reduced MECP2 protein do not gather pups efficiently. This is due to the abnormal formation of structures called perineuronal nets on a specific type of neurons (called parvalbumin+ GABAergic neurons) that block plasticity and prevent learning of the appropriate response. Furthermore, the same neural and molecular mechanisms found earlier in development were also found to mediate learning in adulthood.

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Genetic Cause of Subtle Immune Deficiency Identified

MedicalResearch.com Interview with:

Prof. Adrian Liston (VIB-KU Leuven)

Prof. Adrian Liston

Prof. Adrian Liston
(VIB-KU Leuven)

MedicalResearch.com: What is the background for this study?

Response: With vaccinations, sanitation, antibiotics and general improvements in living standards, infectious disease is no longer a major killer of children. Death or hospitalisation of children from infection is rare in countries with modern health care systems. Those rare events were once thought to be chance outcomes on the roulette of bad luck, but increasingly we are recognising that genetic mutations underlie severe pediatric infections.

In our study we are seeking to identify the mutations and immunological changes that occur in children, causing them to have severe reactions to infectious disease.

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Craniofacial Abnormalities and Rare Muscular Dystrophy Linked To Same Gene

MedicalResearch.com Interview with:
Natalie Shaw, MD, MMSc
National Institute of Environmental Health Sciences
Research Triangle Park, North Carolina and
Harrison Brand, PhD
Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research
Massachusetts General Hospital, Boston
Massachusetts, USA.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Congenital arhinia, or absence of the nose and olfactory system, is an extremely rare malformation, often accompanied by defects in the eyes and reproductive system. Arhinia has been reported in only 80 patients in the past century and though a genetic cause had been suspected, no previous study had identified a plausible genetic candidate.

Through an international collaboration among clinicians and investigators spanning 10 different countries, we were able to assemble a cohort of 40 arhinia patients. Using whole-exome sequencing, we found that 84% of the patients had rare mutations in the same gene – SMCHD1. Further, modeling studies based on patient cells and SMCHD1 knockdown in zebrafish strongly support a role for the gene in arhinia.

We were surprised by this discovery because mutations that impair SMCHD1 function are known to interact with other regions of the genome to cause a type of muscular dystrophy (FSHD2) that does not affect the bones or cartilage of the face. Deep phenotyping of our cohort revealed that individuals with arhinia can in fact develop FSHD2, but it is still unclear why individuals with FSHD2 do not have arhinia.

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Whole Genome Sequencing Speeds Analysis of Shigella Outbreak in California

Dr-Varvara-Kozyreva.jpg

Dr. Varvara Kozyreva

MedicalResearch.com Interview with:
Varvara Kozyreva, PhD
Research Scientist Supervisor I
Genotyping Unit
Foodborne & Waterborne Diseases Section (FWDS)
Microbial Diseases Laboratory Program (MDL)
Division of Communicable Disease Control (DCDC)
Center for Infectious Diseases (CID)
California Department of Public Health (CDPH)
Richmond, CA 94804
California Department of Pubic Health

MedicalResearch.com: What is the background for this study?

CDPH Response: Two large shigellosis outbreaks occurred in San Diego and San Joaquin Counties of California in 2014-2015.

Shigellosis is caused by bacteria of Shigella genus and manifests itself as abdominal pain, diarrhea and other gastrointestinal symptoms. Each year, shigellosis causes around 500,000 infections, 6,000 hospitalizations and 70 deaths in the U.S. The shigellosis outbreaks in California were caused by a rare strain of Shiga-toxin producing Shigella sonnei bacteria. Shigella sonnei normally causes a relatively mild disease and is not known to produce Shiga-toxin. The emergence of this Shiga-toxin producing strain in California was unusual and concerning that shigellosis could become more severe in the future.

The California Department of Public Health Microbial Diseases Laboratory in collaboration with UC Davis tried to understand the origin of the Shigella sonnei strains circulating in California, how the bacteria acquired the Shiga-toxin gene and antibiotic resistance, as well as the relationships of California strains to other lineages around the world. This was the first major whole-genome study of Shigella sonnei bacteria in North America. In order to accomplish this we have sequenced and analyzed genomes of the recent outbreak strains as well as historical Shigella sonnei isolates from our archive going back as far as 1980. We also compared the genomes of California bacteria to other Shigella sonnei genomes from around the world. Among recent isolates we found two distinct outbreak populations: the Shiga-toxin producing strain primarily localized to San Diego and the San Joaquin Valley area, and the strain from the San Francisco Bay Area remarkable for its resistance to broad range of antibiotics.

MedicalResearch.com:  What are the main findings?

CDPH Response: Comprehensive analysis of genomes revealed a common origin of the toxin-producing strains of Shigella sonnei and their connection to earlier strains circulating in California. We learned that these microorganisms were not introduced to California but have originated locally.

It appeared that the toxin gene was introduced to Shigella sonnei with the Shiga-toxin encoding bacteriophage, the virus of bacteria, which interjected itself into Shigella sonnei genome. Most likely this happened via genetic exchange with Escherichia coli and other Shigella species. Furthermore, the bacteriophage in Shigella sonnei from California was very similar to a bacteriophage of Escherichia coli strain, which has caused a large outbreak in Europe in 2011.

 MedicalResearch.com: What should readers take away from this report?

CDPH Response: Whole Genome Sequencing (WGS) of Shigella sonnei allowed in-depth analysis of outbreak strains in California. The knowledge helped strengthen earlier epidemiological analysis of the outbreaks and understand the emerging trends in Shigella sonnei populations circulating in California.

The recent shigellosis outbreaks in California are characterized by two trends: 1) an acquisition of a new virulence factor (Shiga-toxin) by a local bacteria and 2) introduction of the antibiotic-resistant strain from abroad. It demonstrates two possible ways for the pathogens of high public health concern to emerge. This highlights the importance of monitoring the emergence and dissemination of the virulence and antibiotic resistance genetic determinants as well as shifts in local pathogen populations and flow of the bacterial strains between the countries and continents.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

CDPH Response:  Whole Genome Sequencing (WGS) of Shigella sonnei allowed in-depth analysis of outbreak strains in California. The knowledge helped strengthen earlier epidemiological analysis of the outbreaks and understand the emerging trends in Shigella sonnei populations circulating in California.

The recent shigellosis outbreaks in California are characterized by two trends: 1) an acquisition of a new virulence factor (Shiga-toxin) by a local bacteria and 2) introduction of the antibiotic-resistant strain from abroad. It demonstrates two possible ways for the pathogens of high public health concern to emerge. This highlights the importance of monitoring the emergence and dissemination of the virulence and antibiotic resistance genetic determinants as well as shifts in local pathogen populations and flow of the bacterial strains between the countries and continents.

MedicalResearch.com: Is there anything else you would like to add:
CDPH Response:
1. Additional genome analysis of Shigella sonnei is needed to find out if other bacterial traits influence their pathogenic properties.
2. Researchers should foster communications with the healthcare professionals to increase awareness about the potential for serious infectious due to Shigella sonnei.
3. More widespread use of Whole Genome Sequencing (WGS) in public health laboratories would help outbreak investigations, characterization of pathogenic properties of the bacteria and detection of antibiotic resistance genes. This would create a more complete picture of the bacterial world surrounding us, and in turn, help to protect public health

Citation:

Recent Outbreaks of Shigellosis in California Caused by Two Distinct Populations of Shigella sonnei with either Increased Virulence or Fluoroquinolone Resistance
Varvara K. Kozyreva, Guillaume Jospin, Alexander L. Greninger, James P. Watt, Jonathan A. Eisen, Vishnu Chaturvedi
Melanie Blokesch, Editor
DOI: 10.1128/mSphere.00344-16

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