Trunk and Branch Drivers Distinguish Early vs Late Mutations in Hepatocellular Carcinoma

MedicalResearch.com Interview with:
Sara Torrecilla Recio

PhD Student
Mount Sinai Liver Cancer Program – Division of Liver Diseases Icahn School of Medicine at Mount Sinai
New York, NY

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

Response: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, which represents the second-leading cause of cancer related death worldwide. The landscape of molecular alterations in HCC has been thoroughly explored using next-generation sequencing technologies in single biopsies of tumors. However, in the recent years it has been demonstrated that not all the regions of a tumor harbor the same molecular alterations. This intra-tumor heterogeneity may lead to a misinterpretation of the molecular landscape of the malignancy since not all the molecular alterations would be captured by single-biopsies.

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Gene Linked To X-linked Intellectual Disability Identified In Less Than A Day

MedicalResearch.com Interview with:
Daryl Armstrong Scott, M.D., Ph.D
Associate Professor
Molecular and Human Genetics
Baylor College of Medicine
Houston, TX, US

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

Response: This case started with a male child with intellectual disability, developmental delay, hypotonia, hypermobile joints and relative macrocephaly (large head size). Clinical testing showed that he carried a small deletion on chromosome Xp11.22. Since the deleted region had not been previously associated with human disease, the patient was referred to our clinic for additional testing. However, a more detailed analysis revealed that mice that were missing one of the genes located in the deletion interval, Maged1, had neurocognitive and neurobehavioral problems. This sparked additional inquiries which resulted in the identification of three other males from two other families who carried small, overlapping Xp11.22 deletions and had similar features. In all cases, their deletions were inherited from their asymptomatic mothers.

We concluded that deletion of an ~430 kb region on chromosome Xp11.22 that encompasses two pseudogenes (CENPVL1 and CENPVL2) and two protein-coding genes (MAGED1 and GSPT2) causes a novel, syndromic form of X-linked intellectual disability characterized by developmental delay, hypotonia, hypermobile joints and relative macrocephaly.

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New Breast Cancer Genes May Identify Women Who Can Benefit From Enhanced Screening

MedicalResearch.com Interview with:

Fergus J. Couch, Ph.D. Zbigniew and Anna M. Scheller Professor of Medical Research Chair, Division of Experimental Pathology Department of Laboratory Medicine and Pathology Mayo Clinic Rochester, MN 55905

Dr. Couch

Fergus J. Couch, Ph.D.
Zbigniew and Anna M. Scheller Professor  of Medical Research
Chair, Division of Experimental Pathology
Department of Laboratory Medicine  and Pathology
Mayo Clinic
Rochester, MN

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

Response: The main finding is that RAD51D, BARD1, and MSH6 can now be included in the list of moderate risk breast cancer genes. In contrast, other genes such as MRE11A and RAD50 do not increase risk of breast cancer. In addition, we provide initial estimates of the level of breast cancer risk associated with mutations in the genes that cause breast cancer. The “new” breast cancer genes may now be useful for identifying women who can benefit from enhanced screening. These new data will need to be considered by the National Comprehensive Cancer Network (NCCN) which provides guidelines for clinical management of individuals with mutations in cancer predisposition genes. These results will also be useful for identifying members of families who are at increased risk of breast cancer.

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Gene Involved in Defective Skin Barrier and Eczema and Ichthyosis Identified

MedicalResearch.com Interview with:

Akio Kihara, PhD. Laboratory of Biochemistry Faculty of Pharmaceutical Sciences, Hokkaido University Sapporo, Japan

Dr. Akio Kihara

Akio Kihara, PhD.
Laboratory of Biochemistry
Faculty of Pharmaceutical Sciences, Hokkaido University
Sapporo, Japan

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

Response: The skin barrier is the most powerful defensive mechanism terrestrial animals possess against pathogens and harmful substances such as allergens and pollutants. Recent studies indicate that lipids play a central role in skin barrier formation. Multi-lamellar structures consisting of lipids are formed extracellularly in the stratum corneum, the outermost layer of epidermis, and their high hydrophobicity prevents the invasion of external pathogens and compounds.

The stratum corneum-specific lipid acylceramide is especially important for skin barrier formation. Decreases in acylceramide levels are associated with cutaneous disorders such as ichthyosis and atopic dermatitis. However, the mechanism behind acylceramide production is poorly understood, especially regarding the last step of acylceramide production: i.e., esterification of ω-hydroxyceramide with linoleic acid. This means that the broader picture of the molecular mechanisms behind skin barrier formation still remained unclear.

Although PNPLA1 has been identified as an ichthyosis-causative gene, its function in skin barrier formation remains unresolved. In the present study, we revealed that PNPLA1 catalyzes the last step of acylceramide synthesis. Our finding completes our knowledge of the entire pathway of the acylceramide production, providing important insights into the molecular mechanisms of skin barrier formation.

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26 Additional Genes Linked to Intellectual Disability Identified

MedicalResearch.com Interview with:
Dr. Muhammad Ayub MBBS, MRCPsych, MSc., MD

Professor of Psychiatry Chair Division of Developmental Disabilities
Department of Psychiatry Queens
University Kingston
Kingston ON Canada

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

Response: Intellectual Disability affects about 1 percent of the population worldwide. Genetics play a major role in its etiology. Better understanding of the genetic causes is a necessary step in development of improved diagnosis and treatment. Recessive inheritance where the affected child inherits a defective copy of a gene from both the parents is an important genetic mechanism for prevalence of the disease in populations where within family marriages are common. These types of marital bonds are common in South Asia and Middle Eastern countries. The families where parents are related are an effective resource to study recessive forms of Intellectual Disability.

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Novel Viral Vector Allows Gene Transfer To Correct Hearing Loss

MedicalResearch.com Interview with:

Lukas Landegger MD Molecular Neurotology Laboratory (PI Konstantina Stankovic) Massachusetts Eye and Ear Infirmary

Dr. Landegger

Lukas Landegger MD
Molecular Neurotology Laboratory (PI Konstantina Stankovic)
Massachusetts Eye and Ear Infirmary

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

Response: Genetic hearing loss affects more than 125 million people worldwide and constitutes a major hurdle for language acquisition and child development in general. Technological advances over the last decades, such as cochlear implants, have made it possible for deaf children to partially regain their sense of hearing. However, these devices still have several shortcomings, especially when listeners attempt to understand speech in noise or listen to music.

In establishing Anc80L65 as a reliable vector for gene delivery in the inner ear and releasing the first data demonstrating convincing hearing and vestibular function rescue in mice, we provide a foundation for other researchers interested in assessing the benefits of gene therapy in animal models of human disease.

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Rare Gene Variant Linked To Depressive Symptoms

MedicalResearch.com Interview with:
Najaf Amin, PhD
Erasmus University Medical Center
Netherlands

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

Response: Identifying genetic risk factors for depression has not been easy. Over a decade of genetic research did not yield a single replicable genetic factor for depression. It was only recently that 15 common genetic variants mostly in the non-coding parts of the genome were identified through a large genome-wide association study performed by 23andMe. All of these variants add a very small risk to depression individually (odds ratio < 1.05). These common variants cannot explain the cases that have a family history of depression.

Our hypothesis is that such familial cases are enriched for variants that are rare, lie in the coding region of the genome and thus have a large effect on depression. Such variants are enriched in families and isolated populations and therefore have a higher chance of being discovered compared to more cosmopolitan populations. Through gene-based analysis of rare coding variants we have identified a novel gene NKPD1 that may be relevant for depression. Further, we have noticed that the more deleterious the effect of the variant is on the protein, the larger the effect is on depressive symptoms.

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Colorectal Cancer Risk Model Using Environmental and Genetic Factors

MedicalResearch.com Interview with:

Victor Moreno, PhD. Director of Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Spain Department of Clinical Sciences, Faculty of Medicine University of Barcelona Barcelona, Spain

Dr. Moreno

Victor Moreno, PhD.
Director of Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Spain
Department of Clinical Sciences, Faculty of Medicine
University of Barcelona
Barcelona, Spain

Gemma Ibáñez-Sanz, MD Gastroenterologist. *Cancer Prevention and Control Unit, Catalan Institute of Oncology. L’Hospitalet deLlobregat, Barcelona, SPAIN *Gastroenterology Department, Bellvitge University Hospital-IDIBELL,  L’Hospitalet de Llobregat, Spain

Dr. Ibáñez-Sanz

Gemma Ibáñez-Sanz, MD
Gastroenterologist.
*Cancer Prevention and Control Unit, Catalan Institute of Oncology. L’Hospitalet deLlobregat, Barcelona, SPAIN
*Gastroenterology Department, Bellvitge University Hospital-IDIBELL,
L’Hospitalet de Llobregat, Spain 

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

Response: Colorectal cancer (CRC) screening by faecal occult blood testing has been demonstrated to reduce CRC incidence and mortality, as well as being a cost-effective strategy compared to no screening. Currently, the target population is defined basically by age (≥50 years old), which has been called a ‘one-size-fits-all’ strategy. This strategy implies performing unnecessary screening tests in low-risk people leading to avoidable risks for patients and extra costs for the healthcare system. On the other hand, high-risk patients may receive non-invasive testing, which is a suboptimal screening technique in their case. Several risk prediction models, either for  colorectal cancer or advanced neoplasia, have been previously developed, all with limited discriminating ability.

We have developed a risk stratification model that combines environmental factors with family history and genetic susceptibility. Furthermore, we have assessed the relative contribution of these factors and the utility of the model for risk stratification and public health intervention.

MedicalResearch.com: What are the main findings?

Response: Data from common genetic susceptibility loci could be useful to stratify colorectal cancer screening in average-risk population. Individuals in the top quintile of risk alleles have an 82% increased risk compared to those in the lower quintile. We have estimated the impact of determining an individual environmental and genetic risk score in a Spanish CRC screening population. In our model, although the genetic factors are significant contributors, the modifiable risk factors contribute more strongly. Risk assessment may increase screening participation and adoption of healthier lifestyles.

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

Response: On average, each environmental risk factor increases CRC risk by 35%, while each risk allele only increases it by 7%. This implies that the change of one modifiable risk factor towards healthier lifestyle might offset the effect of 4 risk alleles. Given the fact that environmental factors explain part of the CRC risk, we believe it to be important to give thought to incorporating clinical data to encourage individuals to achieve a healthier lifestyle. As the European Code Against Cancer recommends, and our findings confirm, one should have a healthy diet, a healthy body weight, be physically active and should not smoke or a high consumption of alcohol.

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

Response: Future prospective studies should aim to analyse if stratifying by genetic and lifestyle risk scores is useful and cost-effective to improve screening. Subjects with higher predicted risk should probably start screening earlier and decrease the intervals between tests, while low risk individuals could start later or space more the between test intervals.

MedicalResearch.com: Is there anything else you would like to add? 

Response: Population acceptability of genetic tests is not well known. We are currently recruiting subjects from colorectal cancer screening and gastroenterology clinics in a study called COLSCREEN to assess risk perception and attitudes regarding genetic testing to prevent cancer.

No disclosures

Citation:

Sci Rep. 2017 Feb 24;7:43263. doi: 10.1038/srep43263.

Risk Model for Colorectal Cancer in Spanish Population Using Environmental and Genetic Factors: Results from the MCC-Spain study.

Ibáñez-Sanz G1, Díez-Villanueva A1, Alonso MH1,2, Rodríguez-Moranta F2,3, Pérez-Gómez B2,4,5, Bustamante M2,6, Martin V2,7, Llorca J2,8, Amiano P2,9, Ardanaz E2,10, Tardón A2,11, Jiménez-Moleón JJ2,12, Peiró R2,13, Alguacil J2,14, Navarro C2,15, Guinó E1,2, Binefa G1,2, Navarro PF2,4,5, Espinosa A2,6, Dávila-Batista V7, Molina AJ2,7, Palazuelos C8, Castaño-Vinyals G2,6,16,17, Aragonés N2,4,5, Kogevinas M2,6,16,17,18, Pollán M2,4,5, Moreno V1,2,19.

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

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Gene Expression-based Breast Cancer Index Can Improve Decision Making For ER+ Patients

MedicalResearch.com Interview with:

Tara Sanft, MD Assistant Professor of Medicine (Medical Oncology) Medical Director of Adult Survivorship Yale Cancer Center Survivorship Clinic

Dr. Tara Sanft

Tara Sanft, MD
Assistant Professor of Medicine (Medical Oncology)
Medical Director of Adult Survivorship
Yale Cancer Center Survivorship Clinic 

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

Response: Previous studies have demonstrated the benefit of extended endocrine therapy (EET) for hormone receptor-positive (HR+) breast cancer in preventing late relapse, however that benefit is limited to 3-5% of women where late recurrence was prevented or staved off. However, EET has become common practice and as a result we are exposing many patients to risks of side effects and toxicities associated with anti-estrogen therapies when they may not be benefitting, and, conversely may not be treating the patients that might actually benefit. There is a real need to better identify the patients who are both at most risk of late distant recurrence, and most likely to benefit from EET.

This prospective study included 141 patients with a mean age of 62. In the study, 83% of patients were postmenopausal, 73% were stage I.

Breast Cancer Index (BCI) is a gene expression-based test and is the only currently available validated biomarker that is both prognostic for late distant recurrence and predictive for likelihood of benefit from EET. The purpose of this prospective study was to assess the impact of BCI on: physician EET recommendations; physician confidence; patient satisfaction, anxiety, and decision-conflict; and the cost impact of BCI.

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BRCA Testing Shifts From Cancer Patients to Unaffected Women

MedicalResearch.com Interview with:

Fangjian Guo, MD, PhD Department of Obstetrics and Gynecology Center for Interdisciplinary Research in Women’s Health University of Texas Medical Branch Galveston TX

Dr. Fangjian Guo

Fangjian Guo, MD, PhD
Department of Obstetrics and Gynecology
Center for Interdisciplinary Research in Women’s Health
University of Texas Medical Branch
Galveston TX

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

Response: BRCA testing in patients diagnosed with early-onset breast or ovarian cancer can identify women with high-risk mutations, which can guide treatment. Women who learn they have a high-risk mutation may also want to inform family members that they may also carry a high-risk mutation.

Additionally, BRCA testing can be used to identify high-risk mutation carriers before they develop breast or ovarian cancer. Carriers can then manage their cancer risks with screening (MRI/mammogram), chemoprevention, or prophylactic surgery. Current guidelines recommend BRCA testing for individuals who are considered high-risk for breast or ovarian cancer based on personal or family history.  However, this practice fails to identify most BRCA mutation carriers. It is estimated that more than 90% of mutation carriers have not been identified. One of the issues is that many women who do get tested are actually low-risk and do not have any personal or family history of breast or ovarian cancer.

This study assessed how BRCA testing was used in the US health care system during the past decade. We found that in 2004 most of the tests (75.7%) were performed in patients who had been diagnosed with breast or ovarian cancer. Only 24.3% of tests were performed in unaffected women. However, since 2006, the proportion of BRCA tests performed in unaffected women has increased sharply, with over 60% of the tests performed in unaffected women in 2014.

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Based on Genetic Profile, Longer Adjuvant Treatment Recommended for Some GIST Tumors

MedicalResearch.com Interview with:
Heikki Joensuu, MD

Department of Oncology
Helsinki University Hospital
University of Helsinki
Helsinki, Finland 

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

Response: The randomized Scandinavian Sarcoma Group (SSG) XVIII trial compared three years of adjuvant imatinib to one year of adjuvant imatinib as adjuvant treatments of patients who had undergone macroscopically complete surgery for a GIST with a high risk for tumor recurrence. In this trial, patients treated with 3 years of imatinib had improved overall survival as compared to those who were allocated to one year of adjuvant imatinib. In 2 other randomized trials that compared either 1 year of adjuvant imatinib to one year or placebo, or 2 years of adjuvant imatinib to observation, no improvement in overall survival was found, although in all three trials adjuvant imatinib improved recurrence-free survival (RFS). The reasons for the discrepant findings with respect of overall survival in the 3 trials have been unclear.

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Discovery of New Gene That Causes Sudden Death in Young Athletes

MedicalResearch.com Interview with:
Lia Crotti, MD, PhD

Department of Cardiovascular, Neural and Metabolic Sciences
San Luca Hospital
IRCCS Istituto Auxologico Italiano

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

Response: Sudden cardiac death in one of the major cause of death in Western Countries and among the causes of these deaths in young people under the age of 35, inherited forms of cardiomyopathy have a prominent role. Among these cardiomyopathies, Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) plays a major role. In ARVC, the heart tissue is replaced by fatty and fibrous tissue. This process encourages the development of life-threatening arrhythmias, such as ventricular fibrillation, that causes a cardiac arrest and sudden death in few minutes without a ready device to shock the heart. Intense physical activity favors the progression of the disease and arrhythmias are frequently triggered by adrenergic activation: those are the reason why young athletes with this disease are at high risk.

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