Articles That Are Related to Article:

Exome Sequencing and Unrelated Findings in the Context of Complex Disease Research: Ethical and Clinical Implications


BRCA and Beyond: A Genome-first Approach to Familial Breast Cancer Risk Assessment

Abstract: Breast cancer affects around 12% of women in the Western world, but individual lifetime risks vary significantly within any population. Currently, familial cancer services assess and manage familial breast cancer risk based on the presence of a family history of the condition or the identification of high-risk breast cancer susceptibility alleles. This model of clinical care provides an accurate genetic risk assessment for only the minority of families referred to these services. With increasing access to technologies that interrogate human variation at the genome-wide level, it is envisaged that familial breast cancer risk assessments will in the future assume a genome-first approach. This review discusses and highlights the different components of familial breast cancer risk, which will need to be integrated to make this new model of clinical risk assessment possible. ... Read more

Mitochondrial Disease Genetic Diagnostics: Optimized Whole-Exome Analysis for All MitoCarta Nuclear Genes and the Mitochondrial Genome

Abstract: Discovering causative genetic variants in individual cases of suspected mitochondrial disease requires interrogation of both the mitochondrial (mtDNA) and nuclear genomes. Whole-exome sequencing can support simultaneous dual-genome analysis, although currently available capture kits do not target the mtDNA genome and provide insufficient capture for some nuclear-encoded mitochondrial genes. To optimize interrogation of nuclear and mtDNA genes relevant to mitochondrial biology and disease, a custom SureSelect "Mito-Plus" whole-exome library was formulated by blending RNA "baits" from three separate designs: (A) Agilent Technologies SureSelectXT 50 Mb All Exon PLUS Targeted Enrichment Kit, (B) 16-gene nuclear panel targeting sequences for known MitoCarta proteins not included in the 50 Mb All Exon design, and (C) sequences targeting the entire mtDNA genome. The final custom formulations consisted of a 1:1 ratio of nuclear baits to which a 1 to 1,000-fold diluted ratio of mtDNA genome baits were blended. Patient sample capture libraries were paired-end sequenced on an Illumina HiSeq 2000 system using v3.0 SBS chemistry. mtDNA genome coverage varied depending on the mtDNA:nuclear blend ratio, where a 1:100 ratio provided optimal dual-genome coverage with 10X coverage for over 97.5% of all targeted nuclear regions and 1,000X coverage for 99.8% of the mtDNA genome. mtDNA mutations were reliably detected to at least an 8% heteroplasmy level, as discriminated both from sequencing errors and potential contamination from nuclear mtDNA transcripts (Numts). The "1:100 Mito-Plus Whole-Exome" Agilent capture kit offers an optimized tool for whole-exome analysis of nuclear and mtDNA genes relevant to the diagnostic evaluation of mitochondrial disease. ... Read more

Genetics and Genetic Testing of Dilated Cardiomyopathy: a New Perspective

Abstract: The completion of the Human Genome Project was a landmark achievement, but as clinical genetic testing becomes more mainstream, the extent of remarkable genetic variation is increasingly being appreciated. Newer DNA sequencing technology can now complete the sequencing of an entire human genome several times over in a matter of days, but this will undoubtedly add new challenges to the difficulty of distinguishing true pathogenic variants from benign variants in diagnostic genetics and in the research setting. The recent discovery of the role of titin gene (TTN) mutations in dilated cardiomyopathy (DCM) will make genetic testing in this disease more efficient. Furthermore, better understanding of genotype-phenotype associations will assist clinicians in identifying early stages of disease and providing more appropriate treatments. This high level of complexity requires an expert genetic team to offer counseling and to manage, deliver, and follow-up over time the results of genetic testing, which is particularly important for screening of family members potentially at risk. In DCM, genetic testing may be useful for the identification of non-carriers and asymptomatic carriers, as well as for prevention strategies, sport recommendations, and defibrillator implantation. It can also guide reproductive decision-making including utilization of pre-implantation genetic diagnostic strategies. ... Read more

Implementation of Biomarker-Driven Cancer Therapy: Existing Tools and Remaining Gaps

Abstract: There has been growing interest in biomarker-driven personalized cancer therapy, also known as precision medicine. Recently, dozens of molecular tests, including next generation sequencing, have been developed to detect biomarkers that have the potential to predict response of cancers to particular targeted therapies. However, detection of cancer-related biomarkers is only the first step in the battle. Deciding what therapy options to pursue can also be daunting, especially when tumors harbor more than one potentially actionable aberration. Further, different mutations/variants in a single gene may have different functional consequences, and response to targeted agents may be context dependent. However, early clinical trials with new molecular entities are increasingly conducted in a biomarker-selected fashion, and even when trials are not biomarker-selected, much effort is placed on enrolling patients onto clinical trials where they have the highest probability of response. We review available molecular tests and therapy discerning tools, including tools available for assessing functional consequences of molecular alterations and tools for finding applicable clinical trials, which exist to help bridge the gap between detection of cancer-related biomarker to the initiation of biomarker-matched targeted therapies. ... Read more

Integration of Genomics into Medical Practice

Abstract: Although some have wondered whether the sequencing of the human genome has led to major advances in medicine, in fact there are multiple examples where genomics has been integrated into medical practice. In the area of prevention, genomic approaches are now used for non-invasive prenatal testing of fetal DNA in the maternal circulation, for expanded preconceptional screening for carrier status, for autosomal recessive disorders, and for assessment of risk of common disease. In the area of diagnosis, major advances have been made in cytogenomics and in use of whole exome or whole genome sequencing. In therapeutics, pharmacogenetic testing is now feasible, tumor genome sequencing is being used to guide cancer therapy, and genomic discoveries are enabling development of new targeted therapies. Ultimately it is possible that genome sequencing may be done for all individuals on a routine basis, though there remain significant technical, ethical, and medical systems challenges to be overcome. It is likely that integration of genomics into medical practice will occur gradually over a long period of time, but the process is now well underway. ... Read more

Network Medicine Approaches to the Genetics of Complex Diseases

Abstract: Complex diseases are caused by perturbations of biological networks. Genetic analysis approaches focused on individual genetic determinants are unlikely to characterize the network architecture of complex diseases comprehensively. Network medicine, which applies systems biology and network science to complex molecular networks underlying human disease, focuses on identifying the interacting genes and proteins which lead to disease pathogenesis. The long biological path between a genetic risk variant and development of a complex disease involves a range of biochemical intermediates, including coding and non-coding RNA, proteins, and metabolites. Transcriptomics, proteomics, metabolomics, and other -omics technologies have the potential to provide insights into complex disease pathogenesis, especially if they are applied within a network biology framework. Most previous efforts to relate genetics to -omics data have focused on a single -omics platform; the next generation of complex disease genetics studies will require integration of multiple types of -omics data sets in a network context. Network medicine may also provide insight into complex disease heterogeneity, serve as the basis for new disease classifications that reflect underlying disease pathogenesis, and guide rational therapeutic and preventive strategies. ... Read more

Next Generation Sequencing and the Management of Diffuse Large B-cell Lymphoma: From Whole Exome Analysis to Targeted Therapy

Abstract: Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma, accounting for 30-40% of newly diagnosed non-Hodgkin lymphomas. Historically, DLBCL has been thought to involve recurrent translocations of the IGH gene and the deregulation of rearranged oncogenes. Recent advances in next generation sequencing (NGS) have provided a vast and comprehensive catalogue of cancer genes involved in DLBCL pathogenesis. Whole exome sequencing (WES) of more than two hundred DLBCLs has completely redefined the genetic landscape of the disease by identifying recurrent single nucleotide variants and providing new therapeutic opportunities for the germinal center B-cell like (GCB), activated B-cell like (ABC), or primary mediastinal B-cell (PMBL) molecular subtypes. Some of these somatic mutations target genes that play a crucial role in B-cell function (BCR signaling, NF-κB pathway, NOTCH signaling, Toll-like receptor signaling, and the PI3K pathway), immunity, cell cycle/apoptosis, or chromatin modification. In this review, we present an overview of the mutations recently discovered by NGS in DLBCL and discuss their biological relevance and possible impacts on clinical management. ... Read more

Rotavirus Diversity and Evolution in the Post-Vaccine World

Abstract: Rotaviruses (RVs) are a large genetically diverse population of segmented double-stranded (ds) RNA viruses that are important causes of gastroenteritis in many animal species. The human RVs are responsible for the deaths of nearly 450,000 infants and young children each year, most occurring in developing countries. Recent large-scale sequencing efforts have revealed that the genomes of human RVs typically consist of phylogenetically linked constellations of eleven dsRNA segments. The presence of such preferred constellations indicate that the human RV genes have co-evolved to produce protein sets that work optimally together to support virus replication. Two of the viral genes encode virion outer capsid proteins (VP7 and VP4) whose antigenic properties define the G/P type of the virus. From year-to-year and place-to-place, the G/P type of human RVs associated with disease can fluctuate dramatically, phenomena that can be associated with the presence and behavior of genetically distinct RV clades. The recent introduction of two live attenuated RV vaccines (RotaTeqTM and RotarixTM) into the childhood vaccination programs of various countries has been highly effective in reducing the incidence of RV diarrheal disease. Whether the widespread use of these vaccines will introduce selective pressures on human RVs, triggering genetic and antigenic changes that undermine the effectiveness of vaccinations programs, is uncertain and will require continued surveillance of human RVs. ... Read more

Personalized Cancer Treatment and the Myth of KRAS Wild-type Colon Tumors

Abstract: The impact of KRAS mutations on the efficacy of therapies that target the epidermal growth factor receptor (EGFR) is a major, ongoing area of oncology research, aimed at identifying the best possible treatments for individual colon cancer patients. Because patients with KRAS mutant colorectal tumors rarely respond to anti-EGFR monoclonal antibodies, testing is required to confirm the patient's tumor is KRAS wild-type before utilizing these therapies. Despite being studied for more than 30 years, new information continues to develop regarding KRAS and its role in colon carcinogenesis. This information must be integrated into the development of effective colon cancer treatment strategies. This review will summarize recent evidence that most, if not all, colon tumors encompass at least a subpopulation of KRAS mutant cells, meaning tumors characterized as KRAS wild-type are in most cases tumors with relatively low KRAS mutant tumor cell content. Recent studies support the hypothesis that relapse in advanced colorectal patients treated with EGFR-targeted monoclonal antibody therapy involves the outgrowth of previously undetected KRAS mutant tumor cell populations. Studies investigating the effects of oxidative stress on Ras signaling suggest that the frequent presence of minor KRAS mutant tumor cell populations may be a consequence of hypoxic conditions within tumors, which produce a negative selection against KRAS mutant cells in polyclonal tumors. Thus, the literature and current practices for characterizing tumor KRAS mutation don't accurately reflect the nature of colon tumor KRAS mutation, even though an accurate understanding is critical for identifying the best strategies for intervention. ... Read more

Disorders of Sex Development: Clinically Relevant Genes Involved in Gonadal Differentiation

Abstract: After the characterization of the sex-determining region of Y (SRY) in 1990, there have been an increasing number of genes recognized to play a role in sex development. The most common disorders of sex development (DSD) result from disruption of androgen levels and activity that affect later embryonal development, such as congenital adrenal hyperplasia and androgen insensitivity syndrome. However, genetic diagnosis of mutations affecting early gonadal development is becoming increasingly accessible to clinicians. More powerful genetic techniques are allowing for interrogation of the entire genome for causative changes and it is important to be able to critically assess the flood of genetic data for meaningful information. Recent discoveries have clarified the role of a variety of transcription factors in DSD such as SOX9, SF1, and WT1. Additionally, disruptions of signaling molecules such as hedgehog, WNT, cyclin-dependent kinase, and Ras/MAP kinase are now known to cause DSD. The dosage-dependence of genes involved in gonadal development is a recurrent theme, and genetic changes in promoter and repressor regions are being revealed by chromosomal microarray analysis and other techniques. In some cases, there are multiple different phenotypes caused by deletion, duplication, homozygous, heterozygous, and regulatory-region changes in the same gene. We aim to provide a concise and clinically-applicable overview of recent developments in the understanding of DSD caused by genetic changes affecting gonadal development. ... Read more

Close
Close
E-mail It
Close