BMC Med Genomics 2017 Sep 19;10(1):56. Epub 2017 Sep 19.
Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, New Delhi, -110007, India.
Background: PD is a progressive neurodegenerative disorder commonly treated by levodopa. The findings from genetic studies on adverse effects (ADRs) and levodopa efficacy are mostly inconclusive. Here, we aim to identify predictive genetic biomarkers for levodopa response (LR) and determine common molecular link with disease susceptibility. Read More
BMC Med Genomics 2017 Sep 6;10(1):55. Epub 2017 Sep 6.
State Key Laboratory of Medical Genomics, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
Background: Inhibition of nonsense-mediated mRNA decay (NMD) in tumor cells can suppress tumor growth through expressing new antigens whose mRNAs otherwise are degraded by NMD. Thus NMD inhibition is a promising approach for developing cancer therapies. Apparently, the success of this approach relies on the basal NMD activity in cancer cells. Read More
Background: Formalin fixed paraffin embedded (FFPE) tumor samples are a major source of DNA from patients in cancer research. However, FFPE is a challenging material to work with due to macromolecular fragmentation and nucleic acid crosslinking. FFPE tissue particularly possesses challenges for methylation analysis and for preparing sequencing-based libraries relying on bisulfite conversion. Read More
BMC Med Genomics 2017 Aug 29;10(1):53. Epub 2017 Aug 29.
Integrated Cancer Research Center, School of Biological Sciences, and Parker H. Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, 315 Ferst Dr, Atlanta, GA, 30332, USA.
Background: Gene-fusion or chimeric transcripts have been implicated in the onset and progression of a variety of cancers. Massively parallel RNA sequencing (RNA-Seq) of the cellular transcriptome is a promising approach for the identification of chimeric transcripts of potential functional significance. We report here the development and use of an integrated computational pipeline for the de novo assembly and characterization of chimeric transcripts in 55 primary breast cancer and normal tissue samples. Read More
Background: The implantation of mechanical circulatory support devices in heart failure patients is associated with a systemic inflammatory response, potentially leading to death from multiple organ dysfunction syndrome. Previous studies point to the involvement of many mechanisms, but an integrative hypothesis does not yet exist. Using time-dependent whole-genome mRNA expression in circulating leukocytes, we constructed a systems-model to improve mechanistic understanding and prediction of adverse outcomes. Read More
Background: Preeclampsia is a multifactorial disease with unknown pathogenesis. Even when recent studies explored this disease using several bioinformatics tools, the main objective was not directed to pathogenesis. Additionally, consensus prioritization was proved to be highly efficient in the recognition of genes-disease association. Read More
Background: As genome sequencing technology develops rapidly, there has lately been an increasing need to keep genomic data secure even when stored in the cloud and still used for research. We are interested in designing a protocol for the secure outsourcing matching problem on encrypted data.
Method: We propose an efficient method to securely search a matching position with the query data and extract some information at the position. Read More
Background: Advances in DNA sequencing technologies have prompted a wide range of genomic applications to improve healthcare and facilitate biomedical research. However, privacy and security concerns have emerged as a challenge for utilizing cloud computing to handle sensitive genomic data.
Methods: We present one of the first implementations of Software Guard Extension (SGX) based securely outsourced genetic testing framework, which leverages multiple cryptographic protocols and minimal perfect hash scheme to enable efficient and secure data storage and computation outsourcing. Read More
Background: With the enormous need for federated eco-system for holding global genomic and clinical data, Global Alliance for Genomic and Health (GA4GH) has created an international website called beacon service which allows a researcher to find out whether a specific dataset can be utilized to his or her research beforehand. This simple webservice is quite useful as it allows queries like whether a certain position of a target chromosome has a specific nucleotide. However, the increased integration of individuals genomic data into clinical practice and research raised serious privacy concern. Read More
Background: Cloud computing is becoming the preferred solution for efficiently dealing with the increasing amount of genomic data. Yet, outsourcing storage and processing sensitive information, such as genomic data, comes with important concerns related to privacy and security. This calls for new sophisticated techniques that ensure data protection from untrusted cloud providers and that still enable researchers to obtain useful information. Read More
Background: Edit distance is a well established metric to quantify how dissimilar two strings are by counting the minimum number of operations required to transform one string into the other. It is utilized in the domain of human genomic sequence similarity as it captures the requirements and leads to a better diagnosis of diseases. However, in addition to the computational complexity due to the large genomic sequence length, the privacy of these sequences are highly important. Read More
Background: Whole genome sequencing has become fast, accurate, and cheap, paving the way towards the large-scale collection and processing of human genome data. Unfortunately, this dawning genome era does not only promise tremendous advances in biomedical research but also causes unprecedented privacy risks for the many. Handling storage and processing of large genome datasets through cloud services greatly aggravates these concerns. Read More
Department of Electrical Engineering and Computer Science, Vanderbilt University, 2525 West End Avenue, Suite 800, 37203, Nashville, TN, USA.
Background: Genomic data is increasingly collected by a wide array of organizations. As such, there is a growing demand to make summary information about such collections available more widely. However, over the past decade, a series of investigations have shown that attacks, rooted in statistical inference methods, can be applied to discern the presence of a known individual's DNA sequence in the pool of subjects. Read More
Background: One of the tasks in the iDASH Secure Genome Analysis Competition in 2016 was to demonstrate the feasibility of privacy-preserving queries on homomorphically encrypted genomic data. More precisely, given a list of up to 100,000 mutations, the task was to encrypt the data using homomorphic encryption in a way that allows it to be stored securely in the cloud, and enables the data owner to query the dataset for the presence of specific mutations, without revealing any information about the dataset or the queries to the cloud.
Methods: We devise a novel string matching protocol to enable privacy-preserving queries on homomorphically encrypted data. Read More
Background: Intratumor heterogeneity (ITH) poses an urgent challenge for cancer precision medicine because it can cause drug resistance against cancer target therapy and immunotherapy. The search for trunk mutations that are present in all cancer cells is therefore critical for each patient.
Case Presentation: In this study, we aimed to evaluate the efficiency of multiregional sequencing for the identification of trunk mutations present in all regions of a tumor as a case study. Read More
BMC Med Genomics 2017 Jun 19;10(1):47. Epub 2017 Jun 19.
Department of Medical and Molecular Genetics, King's College London, 8th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.
Background: Rapid advances in scientific research have led to an increase in public awareness of genetic testing and pharmacogenetics. Direct-to-consumer (DTC) genetic testing companies, such as 23andMe, allow consumers to access their genetic information directly through an online service without the involvement of healthcare professionals. Here, we evaluate the clinical relevance of pharmacogenetic tests reported by 23andMe in their UK tests. Read More
Background: Lung cancer is a leading cause of cancer-related death worldwide and is the most commonly diagnosed cancer. Like other cancers, it is a complex and highly heterogeneous disease involving multiple signaling pathways. Identifying potential therapeutic targets is critical for the development of effective treatment strategies. Read More
Background: Many genetic diseases are caused by mutations in non-coding regions of the genome. These mutations are frequently found in enhancer sequences, causing disruption to the regulatory program of the cell. Enhancers are short regulatory sequences in the non-coding part of the genome that are essential for the proper regulation of transcription. Read More
Background: Aspirin Exacerbated Respiratory Disease (AERD) is a chronic medical condition that encompasses asthma, nasal polyposis, and hypersensitivity to aspirin and other non-steroidal anti-inflammatory drugs. Several previous studies have shown that part of the genetic effects of the disease may be induced by the interaction of multiple genetic variants. However, heavy computational cost as well as the complexity of the underlying biological mechanism has prevented a thorough investigation of epistatic interactions and thus most previous studies have typically considered only a small number of genetic variants at a time. Read More
Background: One of the fundamental challenges in cancer is to detect the regulators of gene expression changes during cancer progression. Through transcriptional silencing of critical cancer-related genes, epigenetic change such as DNA methylation plays a crucial role in cancer. In addition, miRNA, another major component of epigenome, is also a regulator at the post-transcriptional levels that modulate transcriptome changes. Read More
Background: The APOE ε4 allele is the most significant common genetic risk factor for late-onset Alzheimer's disease (LOAD). The region surrounding APOE on chromosome 19 has also shown consistent association with LOAD. However, no common variants in the region remain significant after adjusting for APOE genotype. Read More
Background: Breast cancer is a complex disease in which different genomic patterns exists depending on different subtypes. Recent researches present that multiple subtypes of breast cancer occur at different rates, and play a crucial role in planning treatment. To better understand underlying biological mechanisms on breast cancer subtypes, investigating the specific gene regulatory system via different subtypes is desirable. Read More
Background: Complex diseases involve many genes, and these genes are often associated with several different illnesses. Disease similarity measurement can be based on shared genotype or phenotype. Quantifying relationships between genes can reveal previously unknown connections and form a reference base for therapy development and drug repurposing. Read More
Background: Transcriptome analytic tools are commonly used across patient cohorts to develop drugs and predict clinical outcomes. However, as precision medicine pursues more accurate and individualized treatment decisions, these methods are not designed to address single-patient transcriptome analyses. We previously developed and validated the N-of-1-pathways framework using two methods, Wilcoxon and Mahalanobis Distance (MD), for personal transcriptome analysis derived from a pair of samples of a single patient. Read More
Background: Reliable exon recognition is key to the splicing of pre-mRNAs into mature mRNAs. TDP-43 is an RNA-binding protein whose nuclear loss and cytoplasmic aggregation are a hallmark pathology in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). TDP-43 depletion causes the aberrant inclusion of cryptic exons into a range of transcripts, but their extent, relevance to disease pathogenesis and whether they are caused by other RNA-binding proteins implicated in ALS/FTD are unknown. Read More
BMC Med Genomics 2017 May 25;10(1):37. Epub 2017 May 25.
Cancer Research UK Cambridge Centre, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, CB2 0RE, UK.
Background: An increasing number of precision oncology programmes are being launched world-wide. To support this development, we present the Cancer Variant Explorer (CVE), an R package with an interactive Shiny web browser interface.
Results: Leveraging Oncotator and the Drug Gene Interaction Database, CVE offers exploration of variants within single or multiple tumour exomes to identify drivers, resistance mechanisms and to assess druggability. Read More
Background: To realize potential public health benefits from genetic and genomic innovations, understanding how best to implement the innovations into clinical care is important. The objective of this study was to synthesize data on challenges identified by six diverse projects that are part of a National Human Genome Research Institute (NHGRI)-funded network focused on implementing genomics into practice and strategies to overcome these challenges.
Methods: We used a multiple-case study approach with each project considered as a case and qualitative methods to elicit and describe themes related to implementation challenges and strategies. Read More
Background: The growing number of Next Generation Sequencing (NGS) tests is transforming the routine clinical diagnosis of hereditary cancers. Identifying whether a cancer is the result of an underlying disease-causing mutation in a cancer predisposition gene is not only diagnostic for a cancer predisposition syndrome, but also has significant clinical implications in the clinical management of patients and their families.
Methods: Here, we evaluated the performance of MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) in detecting genetic alterations in 76 genes implicated in cancer predisposition syndromes. Read More
Background: The impacts of direct-to-consumer personal genomic testing (PGT) on health behaviors such as diet and exercise are poorly understood. Our investigation aimed to evaluate diet and exercise changes following PGT and to determine if changes were associated with genetic test results obtained from PGT.
Methods: Customers of 23andMe and Pathway Genomics completed a web-based survey prior to receiving PGT results (baseline) and 6 months post-results. Read More
Background: Both ambulatory atrial fibrillation (AF) and post-operative AF (poAF) are associated with substantial morbidity and mortality. Analyzing the tissue-specific gene expression in the left atrium (LA) can identify novel genes associated with AF and further the understanding of the mechanism by which previously identified genetic variants associated with AF mediate their effects.
Methods: LA free wall samples were obtained intraoperatively immediately prior to mitral valve surgery in 62 Caucasian individuals. Read More
Background: Colon cancer, one of the most common causes of cancer-related deaths, arises from adenomatous polyps. In these years, circulating microRNAs (miRNAs) have attracted increasing attention as novel biomarkers for colon cancers. The dysregulated circulating miRNAs in patients with colon adenomas has not been well-understood. Read More
Background: Biliary Atresia (BA) is rare and genetically complex, and the pathogenesis is elusive. The disease course is variable and can represent heterogeneity, which hinders effective disease management. Deciphering the BA phenotypic variance is a priority in clinics and can be achieved by the integrative analysis of genotype and phenotype. Read More
Background: Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, which codes for the dystrophin protein. While progress has been made in defining the molecular basis and pathogenesis of DMD, major gaps remain in understanding mechanisms that contribute to the marked delay in cardiac compared to skeletal muscle dysfunction.
Methods: To address this question, we analyzed cardiac and skeletal muscle tissue microarrays from golden retriever muscular dystrophy (GRMD) dogs, a genetically and clinically homologous model for DMD. Read More
Background: Patient stratification to identify subtypes with different disease manifestations, severity, and expected survival time is a critical task in cancer diagnosis and treatment. While stratification approaches using various biomarkers (including high-throughput gene expression measurements) for patient-to-patient comparisons have been successful in elucidating previously unseen subtypes, there remains an untapped potential of incorporating various genotypic and phenotypic data to discover novel or improved groupings.
Methods: Here, we present HOCUS, a unified analytical framework for patient stratification that uses a community detection technique to extract subtypes out of sparse patient measurements. Read More
Background: Basal-like constitutes an important molecular subtype of breast cancer characterised by an aggressive behaviour and a limited therapy response. The outcome of patients within this subtype is, however, divergent. Some individuals show an increased risk of dying in the first five years, and others a long-term survival of over ten years after the diagnosis. Read More
Background: Mechanisms that inactivate the p53 pathway in Acute Myeloid Leukemia (AML), other than rare mutations, are still not well understood.
Methods: We performed a bioinformatics study of the p53 pathway function at the gene expression level on our collection of 1153 p53-pathway related genes. Publically available Affymetrix data of 607 de-novo AML patients at diagnosis were analyzed according to the patients cytogenetic, FAB and molecular mutations subtypes. Read More
Background: The importance of accurate and affordable mutation calling in fixed pathology samples is becoming increasingly important as we move into the era of personalised medicine. The Affymetrix OncoScan® Array platform is designed to produce actionable mutation calls in archival material.
Methods: We compared calls made using the OncoScan platform with calls made using a custom designed PCR panel followed by next-generation sequencing (NGS), in order to benchmark the sensitivity and specificity of the OncoScan calls in a large cohort of fixed tumour samples. Read More
Background: The distinct types of hematological malignancies have different biological mechanisms and prognoses. For instance, myelodysplastic syndrome (MDS) is generally indolent and low risk; however, it may transform into acute myeloid leukemia (AML), which is much more aggressive.
Methods: We develop a novel network analysis approach that uses expression of eigengenes to delineate the biological differences between these two diseases. Read More
Background: Copy number alterations (CNA) and loss of heterozygosity (LOH) represent a large proportion of genetic structural variations of cancer genomes. These aberrations are continuously accumulated during the procedure of clonal evolution and patterned by phylogenetic branching. This invariably results in the emergence of multiple cell populations with distinct complement of mutational landscapes in tumor sample. Read More
Background: De novo inference of clinically relevant gene function relationships from tumor RNA-seq remains a challenging task. Current methods typically either partition patient samples into a few subtypes or rely upon analysis of pairwise gene correlations that will miss some groups in noisy data. Leveraging higher dimensional information can be expected to increase the power to discern targetable pathways, but this is commonly thought to be an intractable computational problem. Read More
Background: Epithelial to mesenchymal transition, and mimicking processes, contribute to cancer invasion and metastasis, and are known to be responsible for resistance to various therapeutic agents in many cancers. While a number of studies have proposed molecular signatures that characterize the spectrum of such transition, more work is needed to understand how the mesenchymal signature (MS) is regulated in non-epithelial cancers like gliomas, to identify markers with the most prognostic significance, and potential for therapeutic targeting.
Results: Computational analysis of 275 glioma samples from "The Cancer Genome Atlas" was used to identify the regulatory changes between low grade gliomas with little expression of MS, and high grade glioblastomas with high expression of MS. Read More
Background: The PALB2 gene encodes a protein that plays a crucial role in maintaining genomic integrity. Germline inactivating mutations in PALB2 are associated with an increased risk of breast and ovarian cancer. The prevalence and spectrum of recurrent PALB2 germline mutations in breast and ovarian cancer patients from Poland is not clearly defined. Read More
Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating idiopathic disease characterized by unexplained fatigue that fails to resolve with sufficient rest. Diagnosis is based on a list of symptoms and exclusion of other fatigue-related health conditions. Despite a heterogeneous patient population, immune and hypothalamic-pituitary-adrenal (HPA) axis function differences, such as enhanced negative feedback to glucocorticoids, are recurring findings in ME/CFS studies. Read More
Background: Human Phenotype Ontology (HPO) has risen as a useful tool for precision medicine by providing a standardized vocabulary of phenotypic abnormalities to describe presentations of human pathologies; however, there have been relatively few reports combining whole genome sequencing (WGS) and HPO, especially in the context of structural variants.
Methods: We illustrate an integrative analysis of WGS and HPO using an extended pedigree, which involves Prader-Willi Syndrome (PWS), hereditary hemochromatosis (HH), and dysautonomia-like symptoms. A comprehensive WGS pipeline was used to ensure reliable detection of genomic variants. Read More
Background: The use of genome-wide (whole genome or exome) sequencing for population-based newborn screening presents an opportunity to detect and treat or prevent many more serious early-onset health conditions than is possible today.
Methods: The Paediatric Task Team of the Global Alliance for Genomics and Health's Regulatory and Ethics Working Group reviewed current understanding and concerns regarding the use of genomic technologies for population-based newborn screening and developed, by consensus, eight recommendations for clinicians, clinical laboratory scientists, and policy makers.
Results: Before genome-wide sequencing can be implemented in newborn screening programs, its clinical utility and cost-effectiveness must be demonstrated, and the ability to distinguish disease-causing and benign variants of all genes screened must be established. Read More
Background: Familial breast cancer (BC) represents 5 to 10% of all BC cases. Mutations in two high susceptibility BRCA1 and BRCA2 genes explain 16-40% of familial BC, while other high, moderate and low susceptibility genes explain up to 20% more of BC families. The Lebanese reported prevalence of BRCA1 and BRCA2 deleterious mutations (5. Read More
Background: Type 1 diabetes (T1D) is an autoimmune disease and extensive evidence has indicated a critical role of both the innate and the adaptive arms of immune system in disease development. To date most clinical trials of immunomodulation therapies failed to show efficacy. A number of gene expression studies of T1D have been carried out. Read More
Background: Clonal expansion of leukemic cells leads to onset of adult T-cell leukemia (ATL), an aggressive lymphoid malignancy with a very poor prognosis. Infection with human T-cell leukemia virus type-1 (HTLV-1) is the direct cause of ATL onset, and integration of HTLV-1 into the human genome is essential for clonal expansion of leukemic cells. Therefore, monitoring clonal expansion of HTLV-1-infected cells via isolation of integration sites assists in analyzing infected individuals from early infection to the final stage of ATL development. Read More