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Precision medicine genomics

Feixiong Cheng, Han Liang, Atul J Butte, Charis Eng, Ruth Nussinov
Recent remarkable advances in genome sequencing have enabled detailed maps of identified and interpreted genomic variation, dubbed "mutanomes." The availability of thousands of exome/genome sequencing data has prompted the emergence of new challenges in the identification of novel druggable targets and therapeutic strategies. Typically, mutanomes are viewed as one- or two-dimensional. The three-dimensional protein structural view of personal mutanomes sheds light on the functional consequences of clinically actionable mutations revealed in tumor diagnosis and followed up in personalized treatments, in a mutanome-informed manner...
January 2019: Pharmacological Reviews
Vincent Strehlow, Henrike O Heyne, Danique R M Vlaskamp, Katie F M Marwick, Gabrielle Rudolf, Julitta de Bellescize, Saskia Biskup, Eva H Brilstra, Oebele F Brouwer, Petra M C Callenbach, Julia Hentschel, Edouard Hirsch, Peter C Kind, Cyril Mignot, Konrad Platzer, Patrick Rump, Paul A Skehel, David J A Wyllie, Giles E Hardingham, Conny M A van Ravenswaaij-Arts, Gaetan Lesca, Johannes R Lemke
Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals...
December 12, 2018: Brain: a Journal of Neurology
Shiho Takeuchi, Shujiro Okuda
In Japan, the National Cancer Center and university hospitals have initiated next-generation sequencing-based in vitro diagnostic testing for cancer patients as a method of clinical sequencing. Based on the molecular alterations detected, physicians can provide approved targeted therapy and access to investigational drugs for cancer patients. However, interpretation of the clinical significance of genomic alterations remains the most severe bottleneck of precision medicine in cancer. Although many research institutes in the United States are developing knowledge bases for interpretation of the tumor alterations and clinical decisions, these knowledge bases are unsuited as sources of reference in Japan due to differences in the information on approved drugs and implementation of clinical trials...
December 12, 2018: International Journal of Clinical Oncology
Allison M Matthews, Ingrid Blydt-Hansen, Basmah Al-Jabri, John Andersen, Maja Tarailo-Graovac, Magda Price, Katherine Selby, Michelle Demos, Mary Connolly, Britt Drögemoller, Casper Shyr, Jill Mwenifumbo, Alison M Elliott, Jessica Lee, Aisha Ghani, Sylvia Stöckler, Ramona Salvarinova, Hilary Vallance, Graham Sinclair, Colin J Ross, Wyeth W Wasserman, Margaret L McKinnon, Gabriella A Horvath, Helly Goez, Clara D van Karnebeek
PURPOSE: The presentation and etiology of cerebral palsy (CP) are heterogeneous. Diagnostic evaluation can be a prolonged and expensive process that might remain inconclusive. This study aimed to determine the diagnostic yield and impact on management of next-generation sequencing (NGS) in 50 individuals with atypical CP (ACP). METHODS: Patient eligibility criteria included impaired motor function with onset at birth or within the first year of life, and one or more of the following: severe intellectual disability, progressive neurological deterioration, other abnormalities on neurological examination, multiorgan disease, congenital anomalies outside of the central nervous system, an abnormal neurotransmitter profile, family history, brain imaging findings not typical for cerebral palsy...
December 13, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Shingo Kato, Takuo Hayashi, Yoshiyuki Suehara, Haruka Hamanoue, Shoji Yamanaka, Yasushi Ichikawa, Takuma Higurashi, Kenichi Ohashi, Shigeo Yamaguchi, Yumi Nozaki, Yasuhisa Terao, Tsuyoshi Saito
Background: Application of next-generation DNA sequencing (NGS) has recently become increasingly common in the field of clinical oncology in several countries around the world. In Japan also, a system for applying NGS to routine clinical practice is gradually being established. During this process, we introduced in Japan the tumor-profiling MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) assay. Methods: We present here our initial experience with the use of MSK-IMPACT in 68 patients selected from two institutions in Japan between June 2016 and October 2017...
December 12, 2018: Japanese Journal of Clinical Oncology
Valerie A Arboleda, Rena R Xian
The development of rapid parallel sequencing in the last 20 years has begun a revolution in the field of genetics that is changing nearly all disciplines within biology and medicine. Genomic sequencing has become crucial to the diagnosis and clinical management of patients with constitutional diseases and cancer and has quickly become an integral part of the new era of personalized and precision medicine. The precision medicine initiative, released by the NIH in 2015, has catapulted genomic technologies to the forefront of the practice of medicine and biomedical research...
2019: Methods in Molecular Biology
Seung Hoan Choi, Lu-Chen Weng, Carolina Roselli, Honghuang Lin, Christopher M Haggerty, M Benjamin Shoemaker, John Barnard, Dan E Arking, Daniel I Chasman, Christine M Albert, Mark Chaffin, Nathan R Tucker, Jonathan D Smith, Namrata Gupta, Stacey Gabriel, Lauren Margolin, Marisa A Shea, Christian M Shaffer, Zachary T Yoneda, Eric Boerwinkle, Nicholas L Smith, Edwin K Silverman, Susan Redline, Ramachandran S Vasan, Esteban G Burchard, Stephanie M Gogarten, Cecelia Laurie, Thomas W Blackwell, Gonçalo Abecasis, David J Carey, Brandon K Fornwalt, Diane T Smelser, Aris Baras, Frederick E Dewey, Cashell E Jaquish, George J Papanicolaou, Nona Sotoodehnia, David R Van Wagoner, Bruce M Psaty, Sekar Kathiresan, Dawood Darbar, Alvaro Alonso, Susan R Heckbert, Mina K Chung, Dan M Roden, Emelia J Benjamin, Michael F Murray, Kathryn L Lunetta, Steven A Lubitz, Patrick T Ellinor
Importance: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood. Objective: To perform large-scale whole-genome sequencing to identify genetic variants related to AF. Design, Setting, and Participants: The National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high-depth whole-genome sequencing between 2014 and 2017 in 18 526 individuals from the United States, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa...
December 11, 2018: JAMA: the Journal of the American Medical Association
Laurie P Whitsel, John Wilbanks, Mark D Huffman, Jennifer L Hall
This paper focuses on the significant role of government in promoting precision medicine and public health and the potential intersection with healthy living (HL) and population health. Recent research has highlighted the interplay between genes, environments and different exposures individuals and populations experience over a lifetime. These interactions between longitudinal behaviors, epigenetics, and expression of the human genome have the potential to transform health and well-being, even within a single generation...
December 7, 2018: Progress in Cardiovascular Diseases
Seitaro Nomura
Cardiomyopathy, a leading cause of death worldwide, is etiologically and phenotypically heterogeneous and is caused by a combination of genetic and non-genetic factors. Major genomic determinants of dilated cardiomyopathy (DCM) are titin truncating mutations and lamin A/C mutations. Patients with these two genotypes show critically different phenotypes, including penetrance, coexistence with a conduction system abnormality, cardiac prognosis, and treatment response. The transcriptomic and epigenomic characteristics of DCM include activation of the DNA damage response, metabolic reprogramming, and dedifferentiation...
December 4, 2018: Journal of Cardiology
Gabriel Q Shaibi, Iftikhar J Kullo, Davinder P Singh, Richard R Sharp, Eleanna De Filippis, Idali Cuellar, Valentina Hernandez, Sharon Levey, Carmen Radecki Breitkopf, Janet E Olson, James R Cerhan, Lawrence J Mandarino, Stephen N Thibodeau, Noralane M Lindor
AIM: To develop a process for returning medically actionable genomic variants to Latino patients receiving care in a Federally Qualified Health Center. METHODS: Prior to recruitment, researchers met with primary care providers to (1) orient clinicians to the project, (2) establish a process for returning actionable and nonactionable results to participants and providers through the electronic health record, and (3) develop a process for offering clinical decision support for follow-up education and care...
December 6, 2018: Public Health Genomics
Gustavo Rosa Gameiro, Viktor Sinkunas, Gabriel Romero Liguori, José Otavio Costa Auler-Júnior
Health care has changed since the decline in mortality caused by infectious diseases as well as chronic and non-contagious diseases, with a direct impact on the cost of public health and individual health care. We must now transition from traditional reactive medicine based on symptoms, diagnosis and treatment to a system that targets the disease before it occurs and, if it cannot be avoided, treats the disease in a personalized manner. Precision Medicine is that new way of thinking about medicine. In this paper, we performed a thorough review of the literature to present an updated review on the subject, discussing the impact of the use of genetics and genomics in the care process as well as medical education, clinical research and ethical issues...
December 3, 2018: Clinics
Gaia Chiara Mannino, Francesco Andreozzi, Giorgio Sesti
Type 2 diabetes mellitus (T2DM) is a chronic disease that has reached the levels of a global epidemic. In order to achieve optimal glucose control it is often necessary to rely on combination therapy of multiple drugs or insulin, because uncontrolled glucose levels result in T2DM progression and enhanced risk of complications and mortality. Several anti-hyperglycemic agents have been developed over time, and T2DM pharmacotherapy should be prescribed based on suitability for the individual patient's characteristics...
December 4, 2018: Diabetes/metabolism Research and Reviews
Toshifumi Wakai, Pankaj Prasoon, Yuki Hirose, Yoshifumi Shimada, Hiroshi Ichikawa, Masayuki Nagahashi
Numerous technical and functional advances in next-generation sequencing (NGS) have led to the adoption of this technique in conventional clinical practice. Recently, large-scale genomic research and NGS technological innovation have revealed many more details of somatic and germline mutations in solid tumors. This development is allowing for the classification of tumor type sub-categories based on genetic alterations in solid tumors, and based on this information, new drugs and targeted therapies are being administered to patients...
December 4, 2018: International Journal of Clinical Oncology
Winter Spence
Prostate cancer continues to be the most commonly diagnosed cancer among Canadian men. The introduction of routine screening and advanced treatment options have allowed for a decrease in prostate cancer-related mortality, but outcomes following treatment continue to vary widely. In addition, the overtreatment of indolent prostate cancers causes unnecessary treatment toxicities and burdens health care systems. Accurate identification of patients who should undergo aggressive treatment, and those which should be managed more conservatively, needs to be implemented...
December 2018: Journal of Medical Imaging and Radiation Sciences
Ya-Ping Ye, Hong-Li Jiao, Shu-Yang Wang, Zhi-Yuan Xiao, Dan Zhang, Jun-Feng Qiu, Ling-Jie Zhang, Ya-Li Zhao, Ting-Ting Li, Li-Liang, Wen-Ting Liao, Yan-Qing Ding
BACKGROUND: Colorectal cancer (CRC) is one of the most common digestive malignant tumors, and DMTN is a transcriptionally differentially expressed gene that was identified using CRC mRNA sequencing data from The Cancer Genome Atlas (TCGA). Our preliminary work suggested that the expression of DMTN was downregulated in CRC, and the Rac1 signaling pathway was significantly enriched in CRC tissues with low DMTN expression. However, the specific functions and underlying molecular mechanisms of DMTN in the progression of CRC and the upstream factors regulating the downregulation of the gene remain unclear...
December 4, 2018: Journal of Experimental & Clinical Cancer Research: CR
Jie Xiong, Wei-Li Zhao
Natural-killer/T cell lymphoma (NKTCL) represents the most common subtype of extranodal lymphoma with aggressive clinical behavior. Prevalent in Asians and South Americans, the pathogenesis of NKTCL remains to be fully elucidated. Using system biology techniques including genomics, transcriptomics, epigenomics, and metabolomics, novel biomarkers and therapeutic targets have been revealed in NKTCL. Whole-exome sequencing studies identify recurrent somatic gene mutations, involving RNA helicases, tumor suppressors, JAK-STAT pathway molecules, and epigenetic modifiers...
December 4, 2018: Journal of Hematology & Oncology
Zheng Hu, Ding Ma
Cervical cancer is a complex disease caused by both genetic susceptibility and environmental factors. Inherited genomic variance, high-risk human papilloma virus (HPV) infection/integration, genome methylation and somatic mutation could all constitute one machine learning model, laying the ground for molecular classification and the precision medicine of cervical cancer. Therefore, for cervical screening, next generation sequencing (NGS)-based HPV DNA and other molecular tests as well as dynamic machine learning models would accurately predict patients with potential to develop the cancer, thereby reducing the burden of repeated screening...
February 25, 2018: Zhejiang da Xue Xue Bao. Yi Xue Ban, Journal of Zhejiang University. Medical Sciences
Seth J Rotz, Eric Kodish
Recent genomic discoveries have improved our understanding of many hematologic diseases and led to novel therapeutic options for many patients. The rapid decrease in the cost of genomic testing has enabled widespread use of clinical genomic testing. However, these advances are accompanied by concomitant challenging ethical concerns. In pediatrics, issues of informed consent for genomic testing, assent, and permission vary significantly by patient age and comprehension. Broader testing strategies, such as whole-exome or whole-genome sequencing, are more likely to yield incidental findings unrelated to the reason for the initial test, and plans to deal with these results when they occur are increasingly important...
November 30, 2018: Hematology—the Education Program of the American Society of Hematology
Hyesun Park, Mizuki Nishino, Jason L Hornick, Eric D Jacobsen
Histiocytosis describes a group of diseases that have long been considered enigmatic in the history of medicine. Recently, novel genomic analyses have identified somatic oncogenic driver mutations responsible for the pathogenesis of these entities. These discoveries have led to the recharacterization of histiocytoses as neoplastic diseases and have opened a new era of precision medicine approaches for treatment. The histiocytic disorders demonstrate a variety of imaging manifestations involving multiple organ systems, and radiologists play a major role in diagnosis and monitoring...
November 30, 2018: Radiographics: a Review Publication of the Radiological Society of North America, Inc
Jake R Conway, Eric Kofman, Shirley S Mo, Haitham Elmarakeby, Eliezer Van Allen
Immune checkpoint blockade (ICB) therapies, which potentiate the body's natural immune response against tumor cells, have shown immense promise in the treatment of various cancers. Currently, tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are the primary biomarkers evaluated for clinical management of cancer patients across histologies. However, the wide range of responses has demonstrated that the specific molecular and genetic characteristics of each patient's tumor and immune system must be considered to maximize treatment efficacy...
November 29, 2018: Genome Medicine
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