scholarly journals Precision Medicine in Pediatric Cancer: Current Applications and Future Prospects

2018 ◽  
Vol 7 (4) ◽  
pp. 39 ◽  
Author(s):  
Atif Ahmed ◽  
Divya Vundamati ◽  
Midhat Farooqi ◽  
Erin Guest
Keyword(s):  
Pediatric Cancer ◽  
Pediatric Population ◽  
Current Status ◽  
Precision Oncology ◽  
Pediatric Tumors ◽  
Future Prospects ◽  
Clinical Scenarios ◽  
The Individual ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Precision oncologic medicine is an emerging approach for cancer treatment that has recently taken giant steps in solid clinical practice. Recent advances in molecular diagnostics that can analyze the individual tumor’s variability in genes have provided greater understanding and additional strategies to treat cancers. Although tumors can be tested by several molecular methods, the use of next-generation sequencing (NGS) has greatly facilitated our understanding of pediatric cancer and identified additional therapeutic opportunities. Pediatric tumors have a different genetic make-up, with a fewer number of actionable targets than adult tumors. Nevertheless, precision oncology in the pediatric population has greatly improved the survival of patients with leukemia and solid tumors. This review discusses the current status of pediatric precision oncology and the different clinical scenarios in which it can be effectively applied.

scholarly journals Tumor Variant Identification That Accounts for the Unique Molecular Landscape of Pediatric Malignancies

2018 ◽  
Vol 2 (4) ◽  
Author(s):  
Amanda Lorentzian ◽  
Jaclyn A Biegel ◽  
D Gigi Ostrow ◽  
Nina Rolf ◽  
Chi-Chao Liu ◽  
...  
Keyword(s):  
Pediatric Cancer ◽  
Copy Number Variants ◽  
Genetic Alterations ◽  
Precision Oncology ◽  
Pediatric Tumors ◽  
Gene Fusions ◽  
Driver Genes ◽  
Molecular Landscape ◽  
Generation Sequencing ◽  
Variant Identification

Abstract Precision oncology trials for pediatric cancers require rapid and accurate detection of genetic alterations. Tumor variant identification should interrogate the distinctive driver genes and more frequent copy number variants and gene fusions that are characteristics of pediatric tumors. Here, we evaluate tumor variant identification using whole genome sequencing (n = 12 samples) and two amplification-based next-generation sequencing assays (n = 28 samples), including one assay designed to rapidly assess common diagnostic, prognostic, and therapeutic biomarkers found in pediatric tumors. Variant identification by the three modalities was comparable when filtered for 151 pediatric driver genes. Across the 28 samples, the pediatric cancer-focused assay detected more tumor variants per sample (two-sided, P < .05), which improved the identification of potentially druggable events and matched pathway inhibitors. Overall, our data indicate that an assay designed to evaluate pediatric cancer-specific variants, including gene fusions, may improve the detection of target-agent pairs for precision oncology.

scholarly journals Comparison of three commercial decision support platforms for matching of next-generation sequencing results with therapies in patients with cancer

ESMO Open ◽  
2020 ◽  
Vol 5 (5) ◽  
pp. e000872
Author(s):  
Samantha O Perakis ◽  
Sabrina Weber ◽  
Qing Zhou ◽  
Ricarda Graf ◽  
Sabine Hojas ◽  
...  
Keyword(s):  
Decision Support ◽  
Next Generation Sequencing ◽  
Metastatic Breast ◽  
Clinical Decision ◽  
Molecular Data ◽  
Current Status ◽  
Precision Oncology ◽  
Next Generation ◽  
Generation Sequencing ◽  
Tier I

ObjectivePrecision oncology depends on translating molecular data into therapy recommendations. However, with the growing complexity of next-generation sequencing-based tests, clinical interpretation of somatic genomic mutations has evolved into a formidable task. Here, we compared the performance of three commercial clinical decision support tools, that is, NAVIFY Mutation Profiler (NAVIFY; Roche), QIAGEN Clinical Insight (QCI) Interpret (QIAGEN) and CureMatch Bionov (CureMatch).MethodsIn order to obtain the current status of the respective tumour genome, we analysed cell-free DNA from patients with metastatic breast, colorectal or non-small cell lung cancer. We evaluated somatic copy number alterations and in parallel applied a 77-gene panel (AVENIO ctDNA Expanded Panel). We then assessed the concordance of tier classification approaches between NAVIFY and QCI and compared the strategies to determine actionability among all three platforms. Finally, we quantified the alignment of treatment suggestions across all decision tools.ResultsEach platform varied in its mode of variant classification and strategy for identifying druggable targets and clinical trials, which resulted in major discrepancies. Even the frequency of concordant actionable events for tier I-A or tier I-B classifications was only 4.3%, 9.5% and 28.4% when comparing NAVIFY with QCI, NAVIFY with CureMatch and CureMatch with QCI, respectively, and the obtained treatment recommendations differed drastically.ConclusionsTreatment decisions based on molecular markers appear at present to be arbitrary and dependent on the chosen strategy. As a consequence, tumours with identical molecular profiles would be differently treated, which challenges the promising concepts of genome-informed medicine.

scholarly journals Current challenges in the implementation of precision oncology for the management of metastatic colorectal cancer

ESMO Open ◽  
2020 ◽  
Vol 5 (2) ◽  
pp. e000634 ◽  
Author(s):  
Sun Young Kim ◽  
Tae Won Kim
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Precision Oncology ◽  
Controversial Issues ◽  
Considerable Uncertainty ◽  
The Road ◽  
Molecularly Targeted Agents ◽  
On The Road ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Over the last few decades, molecularly targeted agents have been used for the treatment of metastatic colorectal cancer. They have made remarkable contributions to prolonging the lives of patients. The emergence of several biomarkers and their introduction to the clinic have also aided in guiding such treatment. Recently, next-generation sequencing (NGS) has enabled clinicians to identify these biomarkers more easily and reliably. However, there is considerable uncertainty in interpreting and implementing the vast amount of information from NGS. The clinical relevance of biomarkers other than NGS are also subjects of debate. This review covers controversial issues and recent findings on such therapeutics and their molecular targets, including VEGF, EGFR, BRAF, HER2, RAS, actionable fusions, Wnt pathway and microsatellite instability for comprehensive understanding of obstacles on the road to precision oncology in metastatic colorectal cancer.

scholarly journals NTRK Fusions Identified in Pediatric Tumors: The Frequency, Fusion Partners, and Clinical Outcome

2021 ◽  
pp. 204-214
Author(s):  
Xiaonan Zhao ◽  
Chelsea Kotch ◽  
Elizabeth Fox ◽  
Lea F. Surrey ◽  
Gerald B. Wertheim ◽  
...  
Keyword(s):  
Pediatric Cancer ◽  
Genomic Profiling ◽  
Pediatric Tumors ◽  
Receptor Kinase ◽  
Papillary Thyroid ◽  
Thyroid Carcinomas ◽  
Dna And Rna ◽  
Tumor Types ◽  
Tyrosine Receptor Kinase ◽  
Generation Sequencing

PURPOSE Neurotrophic tyrosine receptor kinase (NTRK) fusions have been described as oncogenic drivers in a variety of tumors. However, little is known about the overall frequency of NTRK fusion in unselected pediatric tumors. Here, we assessed the frequency, fusion partners, and clinical course in pediatric patients with NTRK fusion–positive tumors. PATIENTS AND METHODS We studied 1,347 consecutive pediatric tumors from 1,217 patients who underwent tumor genomic profiling using custom-designed DNA and RNA next-generation sequencing panels. NTRK fusions identified were orthogonally confirmed. RESULTS AND DISCUSSION NTRK fusions were identified in 29 tumors from 27 patients with a positive yield of 2.22% for all patients and 3.08% for solid tumors. Although NTRK2 fusions were found exclusively in CNS tumors and NTRK1 fusions were highly enriched in papillary thyroid carcinomas, NTRK3 fusions were identified in all tumor categories. The most canonical fusion was ETV6-NTRK3 observed in 10 patients with diverse types of tumors. Several novel NTRK fusions were observed in rare tumor types, including KCTD16-NTRK1 in ganglioglioma and IRF2BP2-NTRK3 in papillary thyroid carcinomas. The detection of an NTRK fusion confirmed the morphologic diagnosis including five cases where the final tumor diagnosis was largely based on the discovery of an NTRK fusion. In one patient, the diagnosis was changed because of the identification of an ETV6-NTRK3 fusion. One patient with infantile fibrosarcoma was treated with larotrectinib and achieved complete pathologic remission. CONCLUSION NTRK fusions are more frequently seen in pediatric tumors than in adult tumors and involve a broader panel of fusion partners and a wider range of tumors than previously recognized. These results highlight the importance of screening for NTRK fusions as part of the tumor genomic profiling for patients with pediatric cancer.

scholarly journals Precision oncology: a clinical and patient perspective

2021 ◽  
Author(s):  
Ulrik N Lassen ◽  
Lydia E Makaroff ◽  
Albrecht Stenzinger ◽  
Antoine Italiano ◽  
Gilles Vassal ◽  
...  
Keyword(s):  
Patient Perspective ◽  
Treatment Strategies ◽  
Current Status ◽  
Precision Oncology ◽  
Multiple Cancer ◽  
Cytotoxic Treatment ◽  
Cancer Types ◽  
Generation Sequencing

Molecular characterization of tumors has shifted cancer treatment strategies away from nonspecific cytotoxic treatment of histology-specific tumors toward targeting of actionable mutations that can be found across multiple cancer types. The development of high-throughput technologies such as next-generation sequencing, combined with decision support applications and availability of patient databases, has provided tools that optimize disease management. Precision oncology has proven success in improving outcomes and quality of life, as well as identifying and overcoming mechanisms of drug resistance and relapse. Addressing challenges that impede its use will improve matching of therapies to patients. Here we review the current status of precision oncology medicine, emphasizing its impact on patients – what they understand about precision oncology medicine and their hopes for the future.

scholarly journals A GENE FEATURE ENUMERATION APPROACH FOR DESCRIBING HLA ALLELE POLYMORPHISM

2015 ◽  
Author(s):  
Steven J. Mack
Keyword(s):  
Sequence Polymorphism ◽  
Untranslated Regions ◽  
Nucleotide Polymorphism ◽  
Allele Polymorphism ◽  
Hla Polymorphism ◽  
Hla Genotyping ◽  
The Individual ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Gene Feature

HLA genotyping via next generation sequencing (NGS) poses challenges for the use of HLA allele names to analyze and discuss sequence polymorphism. NGS will identify many new synonymous and non- coding HLA sequence variants. Allele names identify the types of nucleotide polymorphism that define an allele (non-synonymous, synonymous and non-coding changes), but do not describe how polymorphism is distributed among the individual features (the flanking untranslated regions, exons and introns) of a gene. Further, HLA alleles cannot be named in the absence of antigen-recognition domain (ARD) encoding exons. Here, a system for describing HLA polymorphism in terms of HLA gene features (GFs) is proposed. This system enumerates the unique nucleotide sequences for each GF in an HLA gene, and records these in a GF enumeration notation that allows both more granular dissection of allele-level HLA polymorphism, and the discussion and analysis of GFs in the absence of ARD-encoding exon sequences.

Comprehensive genomic and transcriptomic profiling of pediatric malignancies using the Tempus xT Next-Generation Sequencing Assay to identify clinically meaningful alterations.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e22002-e22002
Author(s):  
Stephanie Toll ◽  
Aneta Kwiatkowska-Piwowarczyk ◽  
Jeff Schaeffer ◽  
Anna Ewa Schwarzbach ◽  
Stefanie Marie Thomas ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Pediatric Cancer ◽  
Target Identification ◽  
Hematologic Malignancies ◽  
Next Generation ◽  
Pediatric Malignancies ◽  
Dna And Rna ◽  
Molecular Dataset ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

e22002 Background: Our understanding of the genomic makeup of childhood cancers has accelerated over the past decade largely due to next-generation sequencing (NGS) utilized to identify genetic drivers, aid diagnostics and risk stratification, and detect therapeutic targets. Here, we present the genomic and transcriptomic landscape of pediatric malignancies tested with a broad NGS panel at a large commercial CLIA/CAP laboratory, Tempus Labs. Methods: We used the Tempus LENS platform to analyze DNA- and RNA-seq data from a cohort of 150 de-identified records of patients with pediatric cancer aged 0 to 18 years who underwent NGS with the Tempus xT platform. Results: The cohort included 139 solid tumors, 46 of which were central nervous system (CNS) tumors, and 11 hematologic malignancies. A total of 115 samples (77%) had at least one clinically meaningful pathogenic somatic variant detected, with TP53 variants being the most common (n=26; 17.3%). Gene fusions, most commonly EWSR1-FLI1 and KIAA1549-BRAF, were observed in 31 cases (20.7%). Matched tumor/normal testing revealed at least one incidental pathogenic germline variant in six patient records, with two cases harboring two distinct variants. Four cases had tumor mutational burdens (TMBs) greater than 10 mutations/megabase, including two that also exhibited high microsatellite instability (MSI). Conclusions: The Tempus xT tumor/normal-matched platform detects clinically meaningful genomic alterations in pediatric cancers important for diagnosis, prognosis, therapeutic target identification, and incidental germline findings. We continue to accumulate and structure data to meet the need for a large, accessible pediatric cancer clinical and molecular dataset. [Table: see text]

scholarly journals Molecular Tests and Target Therapies in Oncology: recommendations from the Italian workshop

2021 ◽  
Author(s):  
Carmine Pinto ◽  
Mauro Biffoni ◽  
Patrizia Popoli ◽  
Antonio Marchetti ◽  
Paolo Marchetti ◽  
...  
Keyword(s):  
New Technologies ◽  
Opinion Leaders ◽  
Gene Profiling ◽  
Precision Oncology ◽  
Molecular Tests ◽  
Specific Tumor ◽  
Tumor Types ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Tumor Gene

Next-generation sequencing (NGS) and liquid biopsy are new technologies that can allow overall tumor profiling in a single analysis and play an important role in the implementation of precision oncology. However, the lack of guidelines in this setting has limited the development of precision oncology in Italy. This article summarizes recommendations for the appropriate use of NGS in tumor gene profiling, as well as access to tests and target drugs, that were prepared by a group of key opinion leaders and relevant stakeholders. In particular, the need to create laboratory networks capable of carrying out NGS tests in Italy is highlighted. It also appears necessary to establish an adequate reimbursement system for NGS tests. However, the expert panel recommends that the use of NGS tests in clinical practice should be limited to specific tumor types, based on the number and complexity of biomarkers and the availability of treatments.

scholarly journals miPIE: NGS-based Prediction of miRNA Using Integrated Evidence

2018 ◽  
Author(s):  
R.J. Peace ◽  
M. Sheikh Hassani ◽  
J.R. Green
Keyword(s):  
De Novo ◽  
Genomic Sequence ◽  
Prediction Performance ◽  
Data Sets ◽  
Mirna Prediction ◽  
Individual Contributions ◽  
The Individual ◽  
Next Generation Sequencing Ngs ◽  
Ngs Data ◽  
Generation Sequencing

AbstractMethods for the de novo identification of microRNA (miRNA) have been developed using a range of sequence-based features. With the increasing availability of next generation sequencing (NGS) transcriptome data, there is a need for miRNA identification that integrates both NGS transcript expression-based patterns as well as advanced genomic sequence-based methods. While miRDeep2 does examine the predicted secondary structure of putative miRNA sequences, it does not leverage many of the sequence-based features used in state-of-the-art de novo methods. Meanwhile, other NGS-based methods, such as miRanalyzer, place an emphasis on sequence-based features without leveraging advanced expression-based features reflecting miRNA biosynthesis. This represents an opportunity to combine the strengths of NGS-based analysis with recent advances in de novo sequence-based miRNA prediction. We here develop a method, microRNA Prediction using Integrated Evidence (miPIE), which integrates both expression-based and sequence-based features to achieve significantly improved miRNA prediction performance. Feature selection identifies the 20 most discriminative features, 3 of which reflect strictly expression-based information. Evaluation using precision-recall curves, for six NGS data sets representing six diverse species, demonstrates substantial improvements in prediction performance compared to miRDeep2 and miRanalyzer. The individual contributions of expression-based and sequence-based features are also examined and we demonstrate that their combination is more effective than either alone.

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