Challenges of Identifying Clinically Actionable Genetic Variants for Precision Medicine

Advances in genomic medicine have the potential to change the way we treat human disease, but translating these advances into reality for improving healthcare outcomes depends essentially on our ability to discover disease- and/or drug-associated clinically actionable genetic mutations. Integration and manipulation of diverse genomic data and comprehensive electronic health records (EHRs) on a big data infrastructure can provide an efficient and effective way to identify clinically actionable genetic variants for personalized treatments and reduce healthcare costs. We review bioinformatics processing of next-generation sequencing (NGS) data, bioinformatics infrastructures for implementing precision medicine, and bioinformatics approaches for identifying clinically actionable genetic variants using high-throughput NGS data and EHRs.

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Patient Derived Xenografts for Genome-Driven Therapy of Osteosarcoma

Cells ◽

10.3390/cells10020416 ◽

2021 ◽

Vol 10 (2) ◽

pp. 416

Author(s):

Lorena Landuzzi ◽

Maria Cristina Manara ◽

Pier-Luigi Lollini ◽

Katia Scotlandi

Keyword(s):

Clinical Trials ◽

Tumor Heterogeneity ◽

Functional Studies ◽

Ngs Data Analysis ◽

The Many ◽

Orthotopic Xenografts ◽

Next Generation Sequencing Ngs ◽

Ngs Data ◽

Generation Sequencing ◽

Somatic Copy Number Alterations

Osteosarcoma (OS) is a rare malignant primary tumor of mesenchymal origin affecting bone. It is characterized by a complex genotype, mainly due to the high frequency of chromothripsis, which leads to multiple somatic copy number alterations and structural rearrangements. Any effort to design genome-driven therapies must therefore consider such high inter- and intra-tumor heterogeneity. Therefore, many laboratories and international networks are developing and sharing OS patient-derived xenografts (OS PDX) to broaden the availability of models that reproduce OS complex clinical heterogeneity. OS PDXs, and new cell lines derived from PDXs, faithfully preserve tumor heterogeneity, genetic, and epigenetic features and are thus valuable tools for predicting drug responses. Here, we review recent achievements concerning OS PDXs, summarizing the methods used to obtain ectopic and orthotopic xenografts and to fully characterize these models. The availability of OS PDXs across the many international PDX platforms and their possible use in PDX clinical trials are also described. We recommend the coupling of next-generation sequencing (NGS) data analysis with functional studies in OS PDXs, as well as the setup of OS PDX clinical trials and co-clinical trials, to enhance the predictive power of experimental evidence and to accelerate the clinical translation of effective genome-guided therapies for this aggressive disease.

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Mining and Development of Novel SSR Markers Using Next Generation Sequencing (NGS) Data in Plants

Molecules ◽

10.3390/molecules23020399 ◽

2018 ◽

Vol 23 (2) ◽

pp. 399 ◽

Cited By ~ 41

Author(s):

Sima Taheri ◽

Thohirah Lee Abdullah ◽

Mohd Yusop ◽

Mohamed Hanafi ◽

Mahbod Sahebi ◽

...

Keyword(s):

Next Generation Sequencing ◽

Ssr Markers ◽

Next Generation ◽

Next Generation Sequencing Ngs ◽

Ngs Data ◽

Generation Sequencing

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Appendix A: Common File Types Used in Next-Generation Sequencing (NGS) Data Analysis

Next-Generation Sequencing Data Analysis ◽

10.1201/b19532-20 ◽

2016 ◽

pp. 199-202

Keyword(s):

Data Analysis ◽

Next Generation Sequencing ◽

Next Generation ◽

Ngs Data Analysis ◽

Next Generation Sequencing Ngs ◽

Ngs Data ◽

Generation Sequencing

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The ICR96 exon CNV validation series: a resource for orthogonal assessment of exon CNV calling in NGS data

Wellcome Open Research ◽

10.12688/wellcomeopenres.11689.1 ◽

2017 ◽

Vol 2 ◽

pp. 35 ◽

Cited By ~ 7

Author(s):

Shazia Mahamdallie ◽

Elise Ruark ◽

Shawn Yost ◽

Emma Ramsay ◽

Imran Uddin ◽

...

Keyword(s):

Sequencing Data ◽

Targeted Next Generation Sequencing ◽

Negative Results ◽

Targeted Ngs ◽

Predisposition Genes ◽

Next Generation Sequencing Ngs ◽

Ngs Data ◽

Validation Series ◽

Generation Sequencing ◽

Dependent Probe

Detection of deletions and duplications of whole exons (exon CNVs) is a key requirement of genetic testing. Accurate detection of this variant type has proved very challenging in targeted next-generation sequencing (NGS) data, particularly if only a single exon is involved. Many different NGS exon CNV calling methods have been developed over the last five years. Such methods are usually evaluated using simulated and/or in-house data due to a lack of publicly-available datasets with orthogonally generated results. This hinders tool comparisons, transparency and reproducibility. To provide a community resource for assessment of exon CNV calling methods in targeted NGS data, we here present the ICR96 exon CNV validation series. The dataset includes high-quality sequencing data from a targeted NGS assay (the TruSight Cancer Panel) together with Multiplex Ligation-dependent Probe Amplification (MLPA) results for 96 independent samples. 66 samples contain at least one validated exon CNV and 30 samples have validated negative results for exon CNVs in 26 genes. The dataset includes 46 exon CNVs in BRCA1, BRCA2, TP53, MLH1, MSH2, MSH6, PMS2, EPCAM or PTEN, giving excellent representation of the cancer predisposition genes most frequently tested in clinical practice. Moreover, the validated exon CNVs include 25 single exon CNVs, the most difficult type of exon CNV to detect. The FASTQ files for the ICR96 exon CNV validation series can be accessed through the European-Genome phenome Archive (EGA) under the accession number EGAS00001002428.

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AbDiver - A tool to explore the natural antibody landscape to aid therapeutic design

10.1101/2021.11.03.467080 ◽

2021 ◽

Author(s):

Jakub Mlokosiewicz ◽

Piotr Deszynski ◽

Wiktoria Wilman ◽

Igor Jaszczyszyn ◽

Rajkumar Ganesan ◽

...

Keyword(s):

Rational Design ◽

Therapeutic Antibody ◽

Human Antibody ◽

Use Case ◽

Therapeutic Antibodies ◽

Road Map ◽

Antibody Sequence ◽

Next Generation Sequencing Ngs ◽

Ngs Data ◽

Generation Sequencing

Motivation: Rational design of therapeutic antibodies can be improved by harnessing the natural sequence diversity of these molecules. Our understanding of the diversity of antibodies has recently been greatly facilitated through the deposition of hundreds of millions of human antibody sequences in next-generation sequencing (NGS) repositories. Contrasting a query therapeutic antibody sequence to naturally observed diversity in similar antibody sequences from NGS can provide a mutational road-map for antibody engineers designing biotherapeutics. Because of the sheer scale of the antibody NGS datasets, performing queries across them is computationally challenging. Results: To facilitate harnessing antibody NGS data, we developed AbDiver (http://naturalantibody.com/abdiver), a free portal allowing users to compare their query sequences to those observed in the natural repertoires. AbDiver offers three antibody-specific use-cases: 1) compare a query antibody to positional variability statistics precomputed from multiple independent studies 2) retrieve close full variable sequence matches to a query antibody and 3) retrieve CDR3 or clonotype matches to a query antibody. We applied our system to a set of 742 therapeutic antibodies, demonstrating that for each use-case our system can retrieve relevant results for most sequences. AbDiver facilitates the navigation of vast antibody mutation space for the purpose of rational therapeutic antibody de-sign and engineering. Availability: AbDiver is freely accessible at http://naturalantibody.com/abdiver

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ViennaNGS: A toolbox for building efficient next- generation sequencing analysis pipelines

F1000Research ◽

10.12688/f1000research.6157.2 ◽

2015 ◽

Vol 4 ◽

pp. 50 ◽

Cited By ~ 7

Author(s):

Michael T. Wolfinger ◽

Jörg Fallmann ◽

Florian Eggenhofer ◽

Fabian Amman

Keyword(s):

Next Generation Sequencing ◽

Sequence Motif ◽

Software Components ◽

Sequencing Analysis ◽

Next Generation ◽

File Formats ◽

Next Generation Sequencing Analysis ◽

Next Generation Sequencing Ngs ◽

Ngs Data ◽

Generation Sequencing

Recent achievements in next-generation sequencing (NGS) technologies lead to a high demand for reuseable software components to easily compile customized analysis workflows for big genomics data. We present ViennaNGS, an integrated collection of Perl modules focused on building efficient pipelines for NGS data processing. It comes with functionality for extracting and converting features from common NGS file formats, computation and evaluation of read mapping statistics, as well as normalization of RNA abundance. Moreover, ViennaNGS provides software components for identification and characterization of splice junctions from RNA-seq data, parsing and condensing sequence motif data, automated construction of Assembly and Track Hubs for the UCSC genome browser, as well as wrapper routines for a set of commonly used NGS command line tools.

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Clinical results and importance of next-generation sequencing (NGS) in detecting targeted mutations in the treatment of metastatic Lung Cancer: Single center initial results

Medical Science and Discovery ◽

10.36472/msd.v6i12.330 ◽

2019 ◽

Vol 6 (12) ◽

pp. 327-332

Author(s):

Cem Mirili ◽

Çiğdem Kahraman ◽

Ali Yılmaz ◽

Mehmet Bilici ◽

Salim Başol Tekin ◽

...

Keyword(s):

Lung Cancer ◽

Next Generation Sequencing ◽

Genetic Variants ◽

Genetic Variant ◽

Clinical Results ◽

Clinical Effects ◽

Next Generation ◽

Variant Analysis ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

Objective: In Lung cancer (LC), which is one of the most deadly cancers, longer survival has been achieved with targeted agents. For this reason, it is important to find the patients who are suitable for targeted therapies. Next-generation sequencing (NGS) is a method that allows multiple genetic variants to be detected simultaneously by performing massive parallel DNA sequencing at the same time. We wanted to reveal the clinical effects and benefits of genetic variant analysis with NGS for our patients. Material and Methods: Patients with stage 4 non-squamous and not otherwise specified (NOS) Non-small cell LC who underwent genetic variant analysis with NGS were included in the study, retrospectively. Results: Total of the 51 patients, 41 (80.4%) were male and the median age was 64 (35-85) years. According to TNM, 21 (41.2%) patients were stage 4A, 30 (58.8%) patients were stage 4B and 39 (76.5%) patients had adenocarcinoma and 12 (23.5%) had NOS histology. NGS analyzes were performed in median 14 days (8-43) and determined 24 pathogenic variants in 17 (%25) patients: 9EGFR (%17,6), 6PIKC3A (%11,7), 5KRAS (%9,8), 2PTEN (%3,9), 1BRAF (%1,9), 1MET (%1,6) (7 of them concomitantly). Cytotoxic chemotherapy was recommended in 41, anti-EGFR agents in 8 (afatinib in 4, erlotinib in 4 patients) patients and anti-BRAF+MEK inhibitor agent (dabrafenib+trametinib) in 1 patient. Conclusion: With the NGS, in just two weeks, both target and resistance genetic variants of our patients were detected at the same time and individualized treatments were applied. In this way, both time and cost were saved.

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Whole genome sequencing suggests transmission of Corynebacterium diphtheriae-caused cutaneous diphtheria in two siblings, Germany, 2018

Eurosurveillance ◽

10.2807/1560-7917.es.2019.24.2.1800683 ◽

2019 ◽

Vol 24 (2) ◽

Cited By ~ 3

Author(s):

Anja Berger ◽

Alexandra Dangel ◽

Tilmann Schober ◽

Birgit Schmidbauer ◽

Regina Konrad ◽

...

Keyword(s):

Next Generation Sequencing ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Corynebacterium Diphtheriae ◽

Whole Genome ◽

Next Generation ◽

Insect Bites ◽

Next Generation Sequencing Ngs ◽

Ngs Data ◽

Generation Sequencing

In September 2018, a child who had returned from Somalia to Germany presented with cutaneous diphtheria by toxigenic Corynebacterium diphtheriae biovar mitis. The child’s sibling had superinfected insect bites harbouring also toxigenic C. diphtheriae. Next generation sequencing (NGS) revealed the same strain in both patients suggesting very recent human-to-human transmission. Epidemiological and NGS data suggest that the two cutaneous diphtheria cases constitute the first outbreak by toxigenic C. diphtheriae in Germany since the 1980s.

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