scholarly journals Clinical Tumor Sequencing: Opportunities and Challenges for Precision Cancer Medicine

2015 ◽  
pp. e175-e182 ◽  
Author(s):  
Senthilkumar Damodaran ◽  
Michael F. Berger ◽  
Sameek Roychowdhury
Keyword(s):  
Genome Sequencing ◽  
Clinical Care ◽  
Point Mutations ◽  
Genomic Testing ◽  
Genomic Alterations ◽  
Discovery Research ◽  
Challenges And Opportunities ◽  
Cancer Medicine ◽  
Next Generation Sequencing Ngs ◽  
Tumor Genome

Advances in tumor genome sequencing have enabled discovery of actionable alterations leading to novel therapies. Currently, there are approved targeted therapies across various tumors that can be matched to genomic alterations, such as point mutations, gene amplification, and translocations. Tools to detect these genomic alterations have emerged as a result of decreasing costs and improved throughput enabled by next-generation sequencing (NGS) technologies. NGS has been successfully utilized for developing biomarkers to assess susceptibility, diagnosis, prognosis, and treatment of cancers. However, clinical application presents some potential challenges in terms of tumor specimen acquisition, analysis, privacy, interpretation, and drug development in rare cancer subsets. Although whole-genome sequencing offers the most complete strategy for tumor analysis, its present utility in clinical care is limited. Consequently, targeted gene capture panels are more commonly employed by academic institutions and commercial vendors for clinical grade cancer genomic testing to assess molecular eligibility for matching therapies, whereas whole-exome and transcriptome (RNASeq) sequencing are being utilized for discovery research. This review discusses the strategies, clinical challenges, and opportunities associated with the application of cancer genomic testing for precision cancer medicine.

scholarly journals Next generation sequencing (NGS) in oncology: lights and shadows

2016 ◽  
Vol 4 (1) ◽  
pp. 17-19
Author(s):  
Margherita Nannini ◽  
Maria A. Pantaleo
Keyword(s):  
Next Generation Sequencing ◽  
Genome Sequencing ◽  
Next Generation ◽  
Coding Regions ◽  
Oncology Research ◽  
Potential Applications ◽  
Functional Consequences ◽  
Next Generation Sequencing Ngs ◽  
Tumor Genome ◽  
Generation Sequencing

Advances in tumor genome sequencing using next generation sequencing (NGS) technologies have facilitated a greater understanding of the genetic abnormalities involved in cancer development and progression, dramatically changing oncology research. There are several different types of NGS technologies. Whole genome sequencing (WGS) determines the sequence of the complete genome, providing information on both coding and non-coding regions and structural variants. However, use is limited by the large volume of data generated, and associated time and resource costs. Whole exome sequencing (WES) determines the sequence of coding regions only, making it faster and cheaper than WGS, and the functional consequences of variants are easier to interpret. However, all variations in non-coding regions are missed. WGS and WES are often used together to maximize detection of variants. A less costly approach is the use of targeted sequencing, which focuses on particular regions of interest, based on their biological relevance. NGS technologies can also be used to sequence RNA, referred to as RNA-Seq. All these NGS technologies, individually or in combination, have a number of potential applications, including identification of biomarkers, and development of diagnostic and therapeutic strategies. However, although advances have been made, there are a number of limitations to be overcome before NGS technologies are routinely applied in both research and clinical practice.

Incorporating Genomics Into the Care of Patients With Advanced Breast Cancer

2018 ◽  
pp. 56-64 ◽  
Author(s):  
Jeremy Kratz ◽  
Mark Burkard ◽  
Tess O’Meara ◽  
Lajos Pusztai ◽  
Zachary Veitch ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clonal Evolution ◽  
Clinical Care ◽  
Metastatic Breast ◽  
Metastatic Tumor ◽  
Genomic Testing ◽  
Investigational Drug ◽  
Genomic Alterations ◽  
Blood Samples ◽  
Drug Treatments

Metastatic breast cancer is a very heterogeneous disease. Recent advances in genomic sequencing have revealed genetic diversity between patients and across distinct subclonal cell populations within the same patient that may evolve across metastatic tumor sites and during treatment. With the increasing availability of commercial and laboratory-developed tests that can detect genomic alterations from patient tumor and blood samples, translating this knowledge into improved clinical care remains a challenge. The goals of this review are to outline the clinical relevance of tumor genomic heterogeneity and clonal evolution, to help clinicians understand how to interpret genomic testing reports, and to provide an overview of recurrent genomic alterations that may be relevant for clinical trials with investigational drug treatments.

scholarly journals Cancer Genome Interpreter annotates the biological and clinical relevance of tumor alterations

2017 ◽  
Author(s):  
David Tamborero ◽  
Carlota Rubio-Perez ◽  
Jordi Deu-Pons ◽  
Michael P Schroeder ◽  
Ana Vivancos ◽  
...  
Keyword(s):  
Open Access ◽  
Genome Sequencing ◽  
Clinical Relevance ◽  
Cancer Genome ◽  
Cancer Therapies ◽  
Cancer Genes ◽  
Genomic Alterations ◽  
Anti Cancer ◽  
Uncertain Significance ◽  
Tumor Genome

AbstractWhile tumor genome sequencing has become widely available in clinical and research settings, the interpretation of tumor somatic variants remains an important bottleneck. Most of the alterations observed in tumors, including those in well-known cancer genes, are of uncertain significance. Moreover, the information on tumor genomic alterations shaping the response to existing therapies is fragmented across the literature and several specialized resources. Here we present the Cancer Genome Interpreter (http://www.cancergenomeinterpreter.org), an open access tool that we have implemented to annotate genomic alterations and interpret their possible role in tumorigenesis and in the response to anti-cancer therapies.

scholarly journals Whole-genome sequencing of recurrent neuroblastoma reveals somatic mutations that affect key players in cancer progression and telomere maintenance

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Susanne Fransson ◽  
Angela Martinez-Monleon ◽  
Mathias Johansson ◽  
Rose-Marie Sjöberg ◽  
Caroline Björklund ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Mapk Signaling ◽  
Telomere Maintenance ◽  
Whole Genome ◽  
Genomic Alterations ◽  
Cycle Progression

AbstractNeuroblastoma is the most common and deadly childhood tumor. Relapsed or refractory neuroblastoma has a very poor prognosis despite recent treatment advances. To investigate genomic alterations associated with relapse and therapy resistance, whole-genome sequencing was performed on diagnostic and relapsed lesions together with constitutional DNA from seven children. Sequencing of relapsed tumors indicates somatic alterations in diverse genes, including those involved in RAS-MAPK signaling, promoting cell cycle progression or function in telomere maintenance and immortalization. Among recurrent alterations, CCND1-gain, TERT-rearrangements, and point mutations in POLR2A, CDK5RAP, and MUC16 were shown in ≥ 2 individuals. Our cohort contained examples of converging genomic alterations in primary-relapse tumor pairs, indicating dependencies related to specific genetic lesions. We also detected rare genetic germline variants in DNA repair genes (e.g., BARD1, BRCA2, CHEK2, and WRN) that might cooperate with somatically acquired variants in these patients with highly aggressive recurrent neuroblastoma. Our data indicate the importance of monitoring recurrent neuroblastoma through sequential genomic characterization and that new therapeutic approaches combining the targeting of MAPK signaling, cell cycle progression, and telomere activity are required for this challenging patient group.

scholarly journals A study of transposable element-associated structural variations (TASVs) using a de novo-assembled Korean genome

2021 ◽  
Author(s):  
Seyoung Mun ◽  
Songmi Kim ◽  
Wooseok Lee ◽  
Keunsoo Kang ◽  
Thomas J. Meyer ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Genome Assembly ◽  
De Novo ◽  
Personal Genome ◽  
Human Populations ◽  
Whole Genome ◽  
Structural Variations ◽  
Insert Size ◽  
Human Genomes ◽  
Next Generation Sequencing Ngs

AbstractAdvances in next-generation sequencing (NGS) technology have made personal genome sequencing possible, and indeed, many individual human genomes have now been sequenced. Comparisons of these individual genomes have revealed substantial genomic differences between human populations as well as between individuals from closely related ethnic groups. Transposable elements (TEs) are known to be one of the major sources of these variations and act through various mechanisms, including de novo insertion, insertion-mediated deletion, and TE–TE recombination-mediated deletion. In this study, we carried out de novo whole-genome sequencing of one Korean individual (KPGP9) via multiple insert-size libraries. The de novo whole-genome assembly resulted in 31,305 scaffolds with a scaffold N50 size of 13.23 Mb. Furthermore, through computational data analysis and experimental verification, we revealed that 182 TE-associated structural variation (TASV) insertions and 89 TASV deletions contributed 64,232 bp in sequence gain and 82,772 bp in sequence loss, respectively, in the KPGP9 genome relative to the hg19 reference genome. We also verified structural differences associated with TASVs by comparative analysis with TASVs in recent genomes (AK1 and TCGA genomes) and reported their details. Here, we constructed a new Korean de novo whole-genome assembly and provide the first study, to our knowledge, focused on the identification of TASVs in an individual Korean genome. Our findings again highlight the role of TEs as a major driver of structural variations in human individual genomes.

scholarly journals Új lehetőség a szisztolés szívelégtelenség (HFrEF) kezelésében: omecamtiv-mecarbil

2021 ◽  
Vol 51 (2) ◽  
pp. 118-124
Author(s):  
Arnold Péter Ráduly ◽  
Attila Tóth ◽  
Zoltán Papp ◽  
Attila Borbély
Keyword(s):  
Genetic Testing ◽  
Expert Panel ◽  
Clinical Care ◽  
Cardiovascular Disorder ◽  
Chain Gene ◽  
Web Based ◽  
Inherited Cardiomyopathy ◽  
Omecamtiv Mecarbil ◽  
Next Generation Sequencing Ngs ◽  
Population Databases

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disorder worldwide which exhibits considerable genetic heterogeneity. Widespread utilization of next-generation sequencing (NGS) in HCM has uncovered substantial genetic variation and highlighted the importance of a standardized approach to variant interpretation. According to this, accurate and consistent interpretation of sequence variants is essential for effective clinical care for individuals and their families with HCM. With this regard, the 2015 guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) were widely applicable, but several elements lacked specificity for given genes or diseases. The latter guideline was adapted for the most frequent causative HCM gene, the beta myosin heavy chain gene (MYH7) by the ClinGen (Clinical Genome Resource) expert panel, the Inherited Cardiomyopathy Expert Panel. Due to the adaptation, the guideline became gene-specific, with general considerations which are widely adaptable for most of the causative genes in HCM. Based on the modified guideline, web-based interpretation algorithms have been developed which integrate data from population databases and define pathogenicity of different variants independent of the observer, therefore aiding standardized clinical interpretation of genetic testing. The latter approach serves as a basis for recommendation for genetic testing in the recent ACC/AHA HCM guideline published in 2020. The current review is meant to compile the latest advances in HCM genetic testing in clinical practice, while bringing into focus some of the ongoing challenges clinical geneticists are still facing. Although nowadays the interpretation of genetic findings is two steps closer to a more accurate approach due to gene adaptation and automatization, the multitude of putative causative genes have been once again reduced to the 8 sarcomere genes, a backward step.

DNA capture in nanopores for genome sequencing: challenges and opportunities

2012 ◽  
Vol 22 (27) ◽  
pp. 13423 ◽  
Author(s):  
Yuhui He ◽  
Makusu Tsutsui ◽  
Masateru Taniguchi ◽  
Tomoji Kawai
Keyword(s):  
Genome Sequencing ◽  
Challenges And Opportunities ◽  
Dna Capture
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