Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

Rare molecular subtypes of lung cancer

http://www.cancertreatmentreviews.com/article/S0305737223000889/pdf

Strategies for improving detection of circulating tumor DNA using next generation sequencing.

Liquid biopsy (LB) is a promising tool that is rapidly evolving as a standard of care in early and advanced stages of cancer settings. Next-generation sequencing (NGS) methods have become essential in molecular diagnostics and clinical laboratories dealing with LB analytes, i.e., cell-free DNA and RNA. The sensitivity and high-throughput capacity of NGS enable us to overcome technical issues that are mainly attributable to low-abundance (below 1% mutated allelic frequency) tumour genetic material circulating within biological fluids. In this context, the introduction of unique molecular identifiers (UMIs), also known as molecular barcodes, applied to various NGS platforms greatly improved the characterization of rare genetic alterations, as they resulted in a drastic reduction in background noise while maintaining high levels of positive predictive value and sensitivity. Different UMI strategies have been developed, such as single (e.g., safe-sequencing system, Safe-SeqS) or double (duplex-sequencing system, Duplex-Seq) strand-based labelling, and, currently, considerable results corroborate their potential implementation in a routine laboratory. Recently, the US Food and Drug Administration approved the clinical use of two comprehensive UMI-based NGS assays (FoundationOne Liquid CDx and Guardant360 CDx) in cfDNA mutational assessment. However, to definitively translate LB into clinical practice, UMI-based NGS protocols should meet certain feasibility requirements in terms of cost-effectiveness, wet laboratory performance and easy access to web-source and bioinformatic tools for downstream molecular data.

The Opportunities and Challenges of Molecular Tagging Next-Generation Sequencing in Liquid Biopsy

Abstract Microsatellite instability (MSI) occurs across a number of cancers and is associated with different clinical characteristics when compared to microsatellite stable (MSS) cancers. As MSI cancers have different characteristics, routine MSI testing is now recommended for a number of cancer types including colorectal cancer (CRC). Using gene panels for sequencing of known cancer mutations is routinely performed to guide treatment decisions. By adding a number of MSI regions to a small gene panel, the efficacy of simultaneous MSI detection in a series of CRCs was tested. Tumour DNA from formalin-fixed, paraffin-embedded (FFPE) tumours was sequenced using a 23-gene panel kit (ATOM-Seq) provided by GeneFirst. The mismatch repair (MMR) status was obtained for each patient from their routine pathology reports, and compared to MSI predictions from the sequencing data. By testing 29 microsatellite regions in 335 samples the MSI status was correctly classified in 314/319 samples (98.4% concordance), with sixteen failures. By reducing the number of regions in silico, comparable performance could be reached with as few as eight MSI marker positions. This test represents a quick, and accurate means of determining MSI status in FFPE CRC samples, as part of a routine gene mutation assay, and can easily be incorporated into a research or diagnostic setting. This could replace separate mutation and MSI tests with no loss of accuracy, thus improving testing efficiency. 

The ATOM-Seq sequence capture panel can accurately predict microsatellite instability status in formalin-fixed tumour samples, alongside routine gene mutation testing

Liquid biopsy testing utilising Next Generation Sequencing (NGS) is rapidly moving towards clinical adoption for personalised oncology. However, before NGS can fulfil its potential any novel testing approach must identify ways of reducing errors, allowing for separating true low-frequency mutations from procedural artefacts, and be designed to improve upon current technologies while also avoiding their limitations. Popular NGS technologies typically utilise two approaches; PCR and ligation, which have known limitations and seem to have reached a development plateau with only small, stepwise improvements being made. To maximise the ultimate utility of liquid biopsy testing we have developed a highly versatile approach to NGS: Adaptor Template Oligo Mediated Sequencing (ATOM-Seq). ATOM-Seq’s strengths and versatility avoid the major limitations of both PCR- and ligation-based approaches. This technology is ligation free, simple, efficient, flexible, and streamlined, and offers novel advantages that make it perfectly suited for use on highly challenging clinical material. Using reference materials, we demonstrate detection of known SNVs at allele frequencies of 0.1% using as little as 20 ng of DNA, as well as the ability to detect fusions from RNA. We illustrate ATOM-Seq’s suitability for clinical testing by showing high concordance rates between paired cfDNA and FFPE clinical samples.

/pdf/adaptor-template-oligo-mediated-sequencing-atom-seq-a-40fr7wr8m1.pdf

Adaptor Template Oligo-Mediated Sequencing (ATOM-Seq): A versatile and ultra-sensitive UMI-based NGS library preparation technology, for use with cfDNA and cfRNA.

Liquid biopsy testing utilising Next Generation Sequencing (NGS) is rapidly moving towards clinical adoption for personalised oncology. However, before NGS can fulfil its potential any novel testing approach must identify ways of reducing errors, allowing separation of true low-frequency mutations from procedural artefacts, and be designed to improve upon current technologies. Popular NGS technologies typically utilise two DNA capture approaches; PCR and ligation, which have known limitations and seem to have reached a development plateau with only small, stepwise improvements being made. To maximise the ultimate utility of liquid biopsy testing we have developed a highly versatile approach to NGS: Adaptor Template Oligo Mediated Sequencing (ATOM-Seq). ATOM-Seq's strengths and versatility avoid the major limitations of both PCR- and ligation-based approaches. This technology is ligation free, simple, efficient, flexible, and streamlined, and it offers novel advantages that make it perfectly suited for use on highly challenging clinical material. Using reference and clinical materials, we demonstrate detection of known SNVs down to allele frequencies of 0.1% using as little as 20–25 ng of cfDNA, as well as the ability to detect fusions from RNA. We illustrate ATOM-Seq’s suitability for clinical testing by showing high concordance rates between paired cfDNA and FFPE clinical samples.

/pdf/adaptor-template-oligo-mediated-sequencing-atom-seq-is-a-new-adho2qqp7j.pdf

Adaptor Template Oligo-Mediated Sequencing (ATOM-Seq) is a new ultra-sensitive UMI-based NGS library preparation technology for use with cfDNA and cfRNA.

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Adaptor Template Oligo-Mediated Sequencing (ATOM-Seq): A versatile and ultra-sensitive UMI-based NGS library preparation technology, for use with cfDNA and cfRNA.

Adaptor Template Oligo-Mediated Sequencing (ATOM-Seq) is a new ultra-sensitive UMI-based NGS library preparation technology for use with cfDNA and cfRNA.