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Precision medicine genomics

Dorothy Keine, John Q Walker, Brian K Kennedy, Marwan N Sabbagh
INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative condition in which individuals exhibit memory loss, dementia, and impaired metabolism. Nearly all previous single-treatment studies to treat AD have failed, likely because it is a complex disease with multiple underlying drivers contributing to risk, onset, and progression. Here, we explored the efficacy of a multi-therapy approach based on the disease risk factor status specific to individuals with AD diagnosis or concern...
October 18, 2018: Current Aging Science
Konstantina Panoutsopoulou, Margaritis Avgeris, Andreas Scorilas
The elucidation of tumor molecular hallmarks and the identification of novel molecular markers are of first translational priority in breast and ovarian cancer research, aiming to support personalized disease treatment and monitoring decisions. Recent high-throughput studies have revealed that ~80% of the genome is transcribed into RNAs without protein-coding potential, namely non-coding RNAs (ncRNAs), challenging the concept of "junk DNA". Undoubtedly, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) represent the best-studied family classes, emerging as the most powerful gene-expression regulators at epigenetic, transcriptional and post-transcriptional levels...
October 19, 2018: Expert Review of Molecular Diagnostics
Masayuki Nagahashi, Yoshifumi Shimada, Hiroshi Ichikawa, Hitoshi Kameyama, Kazuaki Takabe, Shujiro Okuda, Toshifumi Wakai
Next generation sequencing (NGS) has been an invaluable tool to put genomic sequencing into clinical practice. The incorporation of clinically relevant target sequences into NGS-based gene panel tests has generated practical diagnostic tools that enabled individualized cancer-patient care. The clinical utility of gene panel testing includes investigation of the genetic basis for an individual's response to therapy, such as signaling pathways associated with a response to specific therapies, microsatellite instability and a hypermutated phenotype, and deficiency in the DNA double-strand break repair pathway...
October 18, 2018: Cancer Science
Shingo Suzuki, Swati Ranade, Ken Osaki, Sayaka Ito, Atsuko Shigenari, Yuko Ohnuki, Akira Oka, Anri Masuya, John Harting, Primo Baybayan, Miwako Kitazume, Junichi Sunaga, Satoko Morishima, Yasuo Morishima, Hidetoshi Inoko, Jerzy K Kulski, Takashi Shiina
Although NGS technologies fuel advances in high-throughput HLA genotyping methods for identification and classification of HLA genes to assist with precision medicine efforts in disease and transplantation, the efficiency of these methods are impeded by the absence of adequately-characterized high-frequency HLA allele reference sequence databases for the highly polymorphic HLA gene system. Here, we report on producing a comprehensive collection of full-length HLA allele sequences for eight classical HLA loci found in the Japanese population...
2018: Frontiers in Immunology
Tadayuki Kou, Masashi Kanai, Mayumi Kamada, Masahiko Nakatsui, Shigemi Matsumoto, Yasushi Okuno, Manabu Muto
Recent innovations in next-generation sequencing (NGS) technologies have enabled comprehensive genomic profiling of human cancers in the clinical setting. The ability to profile has launched a worldwide trend known as precision medicine, and the fusion of genomic profiling and pharmacogenomics is paving the way for precision medicine for cancer. The profiling is coupled with information about chemical therapies available to patients with specific genotypes. As a result, the chemogenomic space in play is not only the standard chemical and genome space but also the mutational genome and chemical space...
2018: Methods in Molecular Biology
Guilherme Suarez-Kurtz
Pharmacogenetics, a major component of individualized or precision medicine, relies on human genetic diversity. The remarkable developments in sequencing technologies have revealed that the number of genetic variants modulating drug action is much higher than previously thought and that a true personalized prediction of drug response requires attention to rare mutations (minor allele frequency, MAF<1%) in addition to polymorphisms (MAF>1%) in pharmacogenes. This has major implications for the conceptual development and clinical implementation of pharmacogenetics...
October 11, 2018: Clinics
Audrey E Hendricks, Stephen C Billups, Hamish N C Pike, I Sadaf Farooqi, Eleftheria Zeggini, Stephanie A Santorico, Inês Barroso, Josée Dupuis
A primary goal of the recent investment in sequencing is to detect novel genetic associations in health and disease improving the development of treatments and playing a critical role in precision medicine. While this investment has resulted in an enormous total number of sequenced genomes, individual studies of complex traits and diseases are often smaller and underpowered to detect rare variant genetic associations. Existing genetic resources such as the Exome Aggregation Consortium (>60,000 exomes) and the Genome Aggregation Database (~140,000 sequenced samples) have the potential to be used as controls in these studies...
October 2018: PLoS Genetics
Shaimaa Bakr, Olivier Gevaert, Sebastian Echegaray, Kelsey Ayers, Mu Zhou, Majid Shafiq, Hong Zheng, Jalen Anthony Benson, Weiruo Zhang, Ann N C Leung, Michael Kadoch, Chuong D Hoang, Joseph Shrager, Andrew Quon, Daniel L Rubin, Sylvia K Plevritis, Sandy Napel
Medical image biomarkers of cancer promise improvements in patient care through advances in precision medicine. Compared to genomic biomarkers, image biomarkers provide the advantages of being non-invasive, and characterizing a heterogeneous tumor in its entirety, as opposed to limited tissue available via biopsy. We developed a unique radiogenomic dataset from a Non-Small Cell Lung Cancer (NSCLC) cohort of 211 subjects. The dataset comprises Computed Tomography (CT), Positron Emission Tomography (PET)/CT images, semantic annotations of the tumors as observed on the medical images using a controlled vocabulary, and segmentation maps of tumors in the CT scans...
October 16, 2018: Scientific Data
Alan D Kaye, Thomas Mahakian, Aaron J Kaye, Andrew A Pham, Brendon M Hart, Sonja Gennuso, Elyse M Cornett, Rodney A Gabriel, Richard D Urman
The study of how individual genetic differences, known as polymorphisms, change the pharmacokinetics and pharmacodynamics of drugs is called pharmacogenomics. As the field of pharmacogenetics grows and continues to identify genetic polymorphisms, it is promising that the unmet need in this patient population may soon be addressed with personalized drug therapy based on the patient's genetic composition. Although encouraging, pharmacogenomic testing is underutilized in the United States and is often not covered by insurance companies...
June 2018: Best Practice & Research. Clinical Anaesthesiology
Hairong Huang, Nan Ding, Tingting Yang, Cuidan Li, Xinmiao Jia, Guirong Wang, Jun Zhong, Ju Zhang, Guanglu Jiang, Shuqi Wang, Zhaojing Zong, Wei Jing, Yongliang Zhao, Shaofa Xu, Fei Chen
Background: The increase in MDR-TB severely hampers TB prevention and control in China, a country with the second highest MDR-TB burden globally. The first nationwide drug-resistant TB surveillance program provides an opportunity to comprehensively investigate the epidemiological/drug-resistance characteristics, potential drug-resistance mutations, and effective population changes of Chinese MDR-TB. Methods: We sequenced 357 MDR strains from 4,600 representative TB-positive sputum samples collected from the survey (70 counties in 31 provinces)...
October 15, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Giovanna Morello, Antonio Gianmaria Spampinato, Francesca Luisa Conforti, Sebastiano Cavallaro
Recent landmark publications from our research group outline a transformative approach to defining, studying and treating amyotrophic lateral sclerosis (ALS). Rather than approaching ALS as a single entity, we advocate targeting therapies to distinct "clusters" of patients based on their specific genomic and molecular features. Our findings point to the existence of a molecular taxonomy for ALS, bringing us a step closer to the establishment of a precision medicine approach in neurology practice.
2018: Frontiers in Neuroscience
Lena Dolman, Angela Page, Lawrence Babb, Robert R Freimuth, Harindra Arachchi, Chris Bizon, Matthew Brush, Marc Fiume, Melissa Haendel, David P Hansen, Aleksandar Milosavljevic, Ronak Y Patel, Piotr Pawliczek, Andrew D Yates, Heidi L Rehm
The Clinical Genome Resource (ClinGen)'s work to develop a knowledge base to support the understanding of genes and variants for use in precision medicine and research depends on robust, broadly applicable, and adaptable technical standards for sharing data and information. To forward this goal, ClinGen has joined with the Global Alliance for Genomics and Health (GA4GH) to support the development of open, freely-available technical standards and regulatory frameworks for secure and responsible sharing of genomic and health-related data...
November 2018: Human Mutation
Chin-Sheng Hung, Sheng-Chao Wang, Yi-Ting Yen, Tzong-Huei Lee, Wu-Che Wen, Ruo-Kai Lin
Lung and breast cancer are the leading causes of mortality in women worldwide. The discovery of molecular alterations that underlie these two cancers and corresponding drugs has contributed to precision medicine. We found that CCND2 is a common target in lung and breast cancer. Hypermethylation of the CCND2 gene was reported previously; however, no comprehensive study has investigated the clinical significance of CCND2 alterations and its applications and drug discovery. Genome-wide methylation and quantitative methylation-specific real-time polymerase chain reaction (PCR) showed CCND2 promoter hypermethylation in Taiwanese breast cancer patients...
October 10, 2018: International Journal of Molecular Sciences
Linda M Polfus, Laura M Raffield, Marsha M Wheeler, Russell P Tracy, Leslie A Lange, Guillaume Lettre, Amanda Miller, Adolfo Correa, Russell P Bowler, Joshua C Bis, Shabnam Salimi, Nancy Swords Jenny, Nathan Pankratz, Biqi Wang, Michael H Preuss, Lisheng Zhou, Arden Moscati, Girish N Nadkarni, Ruth J F Loos, Xue Zhong, Bingshan Li, Jill M Johnsen, Deborah A Nickerson, Alex P Reiner, Paul L Auer, Nhlbi Trans-Omics For Precision Medicine Consortium
E-selectin mediates the rolling of circulating leukocytes during inflammatory processes. Previous genome-wide association studies (GWAS) in European and Asian individuals have identified the ABO locus associated with E-selectin levels. Using Trans-Omics for Precision Medicine (TOPMed) whole-genome sequencing (WGS) data in 2,249 African Americans (AAs) from the Jackson Heart Study (JHS), we examined genome-wide associations with soluble E-selectin levels. In addition to replicating known signals at ABO, we identified a novel association of a common loss-of-function, missense variant in FUT6 (rs17855739,p...
October 10, 2018: Human Molecular Genetics
Partha Basu, Asima Mukhopadhyay, Ikuo Konishi
Recent advances in molecular biology of cancer have led to the development of targeted agents, mainly of monoclonal antibodies and small-molecule compounds. Unlike traditional drugs that inhibit DNA synthesis and mitosis, these agents target the signaling pathways of cancer cells, stroma, and vasculature in tumor tissues. For gynecologic cancers, drugs targeting angiogenesis such as anti-VEGF antibody have been used in the treatment of advanced or recurrent ovarian and cervical cancers, and the drugs targeting homologous recombination deficiency such as PARP inhibitors have been approved for maintenance after chemotherapy in platinum-sensitive ovarian cancer...
October 2018: International Journal of Gynaecology and Obstetrics
Linda B Baughn, Kathryn Pearce, Dirk Larson, Mei-Yin Polley, Eran Elhaik, Michael Baird, Colin Colby, Joanne Benson, Zhuo Li, Yan Asmann, Terry Therneau, James R Cerhan, Celine M Vachon, A Keith Stewart, P Leif Bergsagel, Angela Dispenzieri, Shaji Kumar, S Vincent Rajkumar
Multiple myeloma (MM) is two- to three-fold more common in African Americans (AAs) compared to European Americans (EAs). This striking disparity, one of the highest of any cancer, may be due to underlying genetic predisposition between these groups. There are multiple unique cytogenetic subtypes of MM, and it is likely that the disparity is associated with only certain subtypes. Previous efforts to understand this disparity have relied on self-reported race rather than genetic ancestry, which may result in bias...
October 10, 2018: Blood Cancer Journal
Takahiro Maeda
In January 2015, President Obama announced his plan to launch the Precision Medicine Initiative. While precision medicine originally refers to a medical model wherein treatments are tailored to individual patients based on their lifestyle, genetic background, and other molecular and physiological test results, genomics-based oncology is most advanced in terms of clinical implementation. Herein, I discuss the benefit of cancer genome sequencing in the field of hematology/oncology and the associated technical and sociomedical challenges...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
James M Bogenberger, Thomas T DeLeon, Mansi Arora, Daniel H Ahn, Mitesh J Borad
Biliary tracts cancers (BTCs) are a diverse group of aggressive malignancies with an overall poor prognosis. Genomic characterization has uncovered many putative clinically actionable aberrations that can also facilitate the prognostication of patients. As such, comprehensive genomic profiling is playing a growing role in the clinical management of BTCs. Currently however, there is only one precision medicine approved by the US Food and Drug Administration (FDA) for the treatment of BTCs. Herein, we highlight the prevalence and prognostic, diagnostic, and predictive significance of recurrent mutations and other genomic aberrations with current clinical implications or emerging relevance to clinical practice...
2018: NPJ precision oncology
Maria Tsoli, Carol Wadham, Mark Pinese, Tim Failes, Swapna Joshi, Emily Mould, Julia X Yin, Velimir Gayevskiy, Amit Kumar, Warren Kaplan, Paul G Ekert, Federica Saletta, Laura Franshaw, Jie Liu, Andrew Gifford, Martin A Weber, Michael Rodriguez, Richard J Cohn, Greg Arndt, Vanessa Tyrrell, Michelle Haber, Toby Trahair, Glenn M Marshall, Kerrie McDonald, Mark J Cowley, David S Ziegler
Pediatric high grade gliomas (HGG) are primary brain malignancies that result in significant morbidity and mortality. One of the challenges in their treatment is inter- and intra-tumoral heterogeneity. Precision medicine approaches have the potential to enhance diagnostic, prognostic and/or therapeutic information. In this case study we describe the molecular characterization of a pediatric HGG and the use of an integrated approach based on genomic, in vitro and in vivo testing to identify actionable targets and treatment options...
October 9, 2018: Cancer Biology & Therapy
Min Jin Ha, Sayantan Banerjee, Rehan Akbani, Han Liang, Gordon B Mills, Kim-Anh Do, Veerabhadran Baladandayuthapani
Personalized (patient-specific) approaches have recently emerged with a precision medicine paradigm that acknowledges the fact that molecular pathway structures and activity might be considerably different within and across tumors. The functional cancer genome and proteome provide rich sources of information to identify patient-specific variations in signaling pathways and activities within and across tumors; however, current analytic methods lack the ability to exploit the diverse and multi-layered architecture of these complex biological networks...
October 8, 2018: Scientific Reports
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