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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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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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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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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DNA Methylation Allows Head and Neck Tumors To Be SubClassified

MedicalResearch.com Interview with:

Jacek Majewski PhD Associate Professor Department of Human Genetics McGill University and Genome Quebec Innovation Centre Montreal, Canada

Dr. Jacek Majewski

Jacek Majewski PhD
Associate Professor
Department of Human Genetics
McGill University and Genome Quebec Innovation Centre
Montreal, Canada 

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

Response: Our lab, in collaboration with Dr. Nada Jabado, has been investigating the molecular genetics of pediatric glioblastoma – a deadly brain cancer. Several years ago, in the majority of our patients’ tumors we discovered mutations in genes that encode histone proteins. Those mutations disrupt the epigenome – that is the way the DNA is modified, silenced, or activated in the cancer cells. It appears that epigenome-modifying mutations are particularly important in pediatric cancers, and our hypothesis is that they act by diverting the normal developmental pathways into unrestrained proliferation. Many other studies have highlighted the significance of epigenome disruption in a number of cancers.

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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

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

More Medical Research Interviews on MedicalResearch.com

Improved Resolution of Disease Phenotypes With Multilocus Genomic Variation

MedicalResearch.com Interview with:
Jennifer E Posey MD, PhD

Assistant Professor
Department of Molecular and Human Genetics
Baylor College of Medicine

Tamar Harel MD, PhD
Clinical Genetics Academic Research Fellow
Department of Molecular and Human Genetics
Baylor College of Medicine

Current affiliation:
Department of Genetic and Metabolic Diseases
Hadassah-Hebrew University Medical Center
Jerusalem, Israel

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

Response: As physician scientists and geneticists, our goal is to understand how genetic variation in each of us can impact health and disease. Physicians are often taught that the simplest explanation for a medical condition is the most correct explanation, and have historically searched for a single unifying diagnosis. However, in our own practice, we have met – and learned from – individuals who have more than one genetic condition affecting their health.

In the past, it was difficult for physicians to diagnose such individuals. Genetic testing required a physician to recognize the potential for more than one genetic diagnosis in an individual. Single-gene and gene panel testing provided an additional barrier to accurate diagnoses, as they are more narrow in scope, and more than one molecular test was often needed to identify all conditions. Targeted testing also required a physician to accurately pre-suppose which combination of genetic conditions was most likely, and choose the correct targeted tests.

The clinical availability of whole exome sequencing (WES) has removed these barriers: WES is a broad-based, unbiased analysis of an individual’s genetic variation that does not pre-suppose a specific genetic cause. If analysis is pursued systematically, WES can identify more than one genetic diagnosis in an individual, even when not suspected.
In our study, we have been able to assess the frequency with which individuals can have more than one genetic diagnosis, and have begun to understand how genetic variation at more than one place in the genome can affect how a condition may present. We found that among 7,374 individuals referred for WES, 2,076 (28%) had a molecular diagnosis. Of these 2,076, 5% had two, three, or four molecular diagnoses. In our analyses of the clinical features that may be observed in an individual with two genetic conditions, we found that pairs of diagnoses with overlapping clinical features may be incompletely diagnosed as having one or the other condition, and pairs of diagnoses with very distinct clinical features may be erroneously diagnosed in the clinic as having an entirely new condition.
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Schizophrenia: SynCav1 As Potential Target To Restore Neuron Function

MedicalResearch.com Interview with:

Brian P. Head, MS, PhD Associate Professor, UCSD Research Scientist, VASDHS Department of Anesthesiology VA San Diego Healthcare System San Diego, CA 92161-9125

Dr. Brian Head

Brian P. Head, MS, PhD
Associate Professor, UCSD
Research Scientist, VASDHS
Department of Anesthesiology
VA San Diego Healthcare System
San Diego, CA 92161-9125

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

Response: DISC1 is a schizophrenia associated gene originally identified in a Scottish family. DISC1 protein is highly expressed in the developing brain and in the dentate gyrus of the adult hippocampus, and is involved in neuritogenesis and neuronal signaling. DISC1 is located in multiple intracellular locations including axons and synapses, and loss of DISC1 function causes deficits in neural development, neuronal proliferation, axonal growth, and cytoskeleton modulation, which are consistent with abnormal neural development in schizophrenia.

SynCav1 means synapsin-driven caveolin construct. Synapsin promoter is neuronal specific which allows us to increase caveolin expression-specifically in neurons. We have previously shown that SynCav1 increases neuronal signaling and dendritic growth and arborization in vitro (Head BP JBC 2011), and when delivered in vivo augments functional neuroplasticity and improves learning and memory in adult and aged mice (Mandyam CD Biol Psych 2015).

Since loss of DISC1 function equates to schizophrenic-like symptoms, then decreased DISC1 expression in Cav-1 KO mice agrees with this premise. Thus, loss of Cav-1 increases their likelihood of developing schizophrenia-like symptoms. Because re-espression of Cav-1 restored DISC1 expression as well as expression of key synaptic proteins, this proof-of-concept findings not only builds upon our previously results demonstrating that Cav-1 is critical for neuronal signaling and functional synaptic plasticity but also strongly links Cav-1 with maintaining normal DISC1 expression levels and potentially attenuating schizophrenia-like symptoms.

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Trajectory To Childhood Asthma Begins At Birth

MedicalResearch.com Interview with:

Donata Vercelli, MD Professor of Cellular and Molecular Medicine, University of Arizona Director, Arizona Center for the Biology of Complex Diseases Associate Director, Asthma and Airway Disease Research Center The BIO5 Institute, Rm. 339 Tucson, AZ 85721

Dr. Donata Vercelli

Donata Vercelli, MD
Professor of Cellular and Molecular Medicine
Director, Arizona Center for the Biology of Complex Diseases
Director, Molecular Genomics, Asthma and Airway Disease Research Center
The University of Arizona The BIO5 Institute
Tucson, AZ 85721

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

Response: Asthma is the most prevalent chronic disease of childhood. Epidemiological evidence suggests that the disease often begins during the pre-school years even when chronic symptoms appear much later in life. However, firm criteria to pinpoint how early a child’s trajectory to asthma truly begins are currently lacking. The mechanisms underlying asthma inception also remain largely unknown. Although epigenetic mechanisms likely contribute to asthma pathogenesis, little is known about their role in asthma inception.

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Genetic Factors Link Communication Competence in Childhood With Autism and Schizophrenia

MedicalResearch.com Interview with:

Dr. Beate St Pourcain MSc, PhD(Cardiff) Genetic Epidemiology School of Oral and Dental Sciences MRC Integrative Epidemiology Unit University of Bristol

Dr. Beate St Pourcain

Dr. Beate St Pourcain MSc, PhD(Cardiff)
Genetic Epidemiology
School of Oral and Dental Sciences
MRC Integrative Epidemiology Unit
University of Bristol

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

Response: People with autism and with schizophrenia both have problems interacting and communicating with other people, because they cannot easily initiate social interactions or give appropriate responses in return. On the other hand, the disorders of autism and schizophrenia develop in very different ways. The first signs of Autism Spectrum Disorder (ASD) typically occur during infancy or early childhood, whereas the symptoms of schizophrenia usually do not appear until early adulthood. The researchers asked whether it is possible to disentangle the apparent symptom overlap in ASD and schizophrenia through genetic analyses.

As clinical diagnoses relate to the age of onset of a disorder and do not capture multiple developmental stages, the researchers used a trick. They assumed that there is a continuum between normal and abnormal behaviour and captured social communicative competence – the ability to socially engage with other people successfully – in participants of a population-based birth cohort during development.

Specifically, the researchers studied the genetic overlap between the risk of having these psychiatric disorders and these measures of social communicative competence. Investigating thousands of genetic variants with small effects across the genome, they showed that genes influencing social communication problems during childhood overlap with genes conferring risk for autism, but that this relationship wanes during adolescence. In contrast, genes influencing risk for schizophrenia were most strongly interrelated with genes affecting social competence during later adolescence, in line with the natural history of the disorder.

“The findings suggest that the risk of developing these contrasting psychiatric conditions is strongly related to distinct sets of genes, both of which influence social communication skills, but exert their maximum influence during different periods of development”, explained Beate St Pourcain, senior investigator at the Max Planck Institute and lead author of the study. This is consistent with studies showing that genetic factors underlying social communication behaviour also change to some degree during childhood and adolescence.

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