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 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 A computational method for prioritizing targeted therapies in precision oncology: performance analysis in the SHIVA01 trial

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Istvan Petak ◽  
Maud Kamal ◽  
Anna Dirner ◽  
Ivan Bieche ◽  
Robert Doczi ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Progressive Disease ◽  
Genetic Alterations ◽  
Outcome Data ◽  
Computational Method ◽  
Molecular Profile ◽  
Precision Oncology ◽  
Driver Genes ◽  
Oncology Clinical Trial ◽  
Molecularly Targeted Agents

AbstractPrecision oncology is currently based on pairing molecularly targeted agents (MTA) to predefined single driver genes or biomarkers. Each tumor harbors a combination of a large number of potential genetic alterations of multiple driver genes in a complex system that limits the potential of this approach. We have developed an artificial intelligence (AI)-assisted computational method, the digital drug-assignment (DDA) system, to prioritize potential MTAs for each cancer patient based on the complex individual molecular profile of their tumor. We analyzed the clinical benefit of the DDA system on the molecular and clinical outcome data of patients treated in the SHIVA01 precision oncology clinical trial with MTAs matched to individual genetic alterations or biomarkers of their tumor. We found that the DDA score assigned to MTAs was significantly higher in patients experiencing disease control than in patients with progressive disease (1523 versus 580, P = 0.037). The median PFS was also significantly longer in patients receiving MTAs with high (1000+ <) than with low (<0) DDA scores (3.95 versus 1.95 months, P = 0.044). Our results indicate that AI-based systems, like DDA, are promising new tools for oncologists to improve the clinical benefit of precision oncology.

scholarly journals Precision Oncology in Sarcomas: Divide and Conquer

2019 ◽  
pp. 1-16 ◽  
Author(s):  
Roberto Carmagnani Pestana ◽  
Roman Groisberg ◽  
Jason Roszik ◽  
Vivek Subbiah
Keyword(s):  
Next Generation Sequencing ◽  
Soft Tissue Sarcomas ◽  
Genetic Alterations ◽  
Divide And Conquer ◽  
Precision Oncology ◽  
Next Generation ◽  
Mesenchymal Tumors ◽  
Next Generation Sequencing Technology ◽  
Molecular Abnormalities ◽  
Generation Sequencing

Sarcomas are a heterogeneous group of rare malignancies that exhibit remarkable heterogeneity, with more than 50 subtypes recognized. Advances in next-generation sequencing technology have resulted in the discovery of genetic events in these mesenchymal tumors, which in addition to enhancing understanding of the biology, have opened up avenues for molecularly targeted therapy and immunotherapy. This review focuses on how incorporation of next-generation sequencing has affected drug development in sarcomas and strategies for optimizing precision oncology for these rare cancers. In a significant percentage of soft tissue sarcomas, which represent up to 40% of all sarcomas, specific driver molecular abnormalities have been identified. The challenge to evaluate these mutations across rare cancer subtypes requires the careful characterization of these genetic alterations to further define compelling drivers with therapeutic implications. Novel models of clinical trial design also are needed. This shift would entail sustained efforts by the sarcoma community to move from one-size-fits-all trials, in which all sarcomas are treated similarly, to divide-and-conquer subtype-specific strategies.

scholarly journals From Genetic Alterations to Tumor Microenvironment: The Ariadne’s String in Pancreatic Cancer

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 309 ◽  
Author(s):  
Chiara Bazzichetto ◽  
Fabiana Conciatori ◽  
Claudio Luchini ◽  
Francesca Simionato ◽  
Raffaela Santoro ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Myeloid Cells ◽  
Genetic Alterations ◽  
Molecular Characteristics ◽  
Precision Oncology ◽  
Cancer Type ◽  
Tumor Type ◽  
Driver Genes

The threatening notoriety of pancreatic cancer mainly arises from its negligible early diagnosis, highly aggressive progression, failure of conventional therapeutic options and consequent very poor prognosis. The most important driver genes of pancreatic cancer are the oncogene KRAS and the tumor suppressors TP53, CDKN2A, and SMAD4. Although the presence of few drivers, several signaling pathways are involved in the oncogenesis of this cancer type, some of them with promising targets for precision oncology. Pancreatic cancer is recognized as one of immunosuppressive phenotype cancer: it is characterized by a fibrotic-desmoplastic stroma, in which there is an intensive cross-talk between several cellular (e.g., fibroblasts, myeloid cells, lymphocytes, endothelial, and myeloid cells) and acellular (collagen, fibronectin, and soluble factors) components. In this review; we aim to describe the current knowledge of the genetic/biological landscape of pancreatic cancer and the composition of its tumor microenvironment; in order to better direct in the intrinsic labyrinth of this complex tumor type. Indeed; disentangling the genetic and molecular characteristics of cancer cells and the environment in which they evolve may represent the crucial step towards more effective therapeutic strategies

The clinical impact of performing routine next generation sequencing (NGS) in gastrointestinal stromal tumors (GIST).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11010-11010 ◽  
Author(s):  
Ciara Marie Kelly ◽  
Timothy Geoffrey Bowler ◽  
Sandra P. D'Angelo ◽  
Mark Andrew Dickson ◽  
Mrinal M. Gounder ◽  
...  
Keyword(s):  
Clinical Management ◽  
Intracellular Signaling ◽  
Mitotic Rate ◽  
Genetic Alterations ◽  
Clinical Impact ◽  
Driver Genes ◽  
Primary Tumors ◽  
Cdkn2a Deletion ◽  
Exon 11 ◽  
Molecular Landscape

11010 Background: The majority of GISTs harbor activating mutations in KIT or PDGFRα but the clinical relevance of other genomic alterations is unknown. We sought to determine the clinical impact of performing routine NGS and to describe the molecular landscape in GIST. Methods: From April 2014 to August 2016, 177 patients (pts) consented to an IRB-approved protocol. Tumor and matched normal samples were prospectively analyzed in a CLIA-compliant laboratory, with MSK-IMPACT, a NGS assay of up to 468 cancer-associated genes. Results: 191 samples were analyzed. NGS was most often performed in the setting of advanced disease (n = 108 (57%)). The primary tumor was most commonly tested (n = 120 (63%)). NGS guided clinical management in 79% (n = 150) of cases [matched therapy (MT) offered, n = 120/150 (80%); MT not offered, n = 24/150 (16%)]. In 25/41 cases (61%) where NGS did not influence management, treatment was not indicated because the GISTs were low risk. Most samples had ≤ 3 mutations (muts) (range: 0-17). Actionable muts were identified in 155/191 samples (81%). These included muts in KIT, PDGFRα and BRAF [oncoKB stratification: level 1 (84%), 2A (13%), 2B (2%), 3A(1%)]. 33/177 pts did not have a KIT/ PDGFRα mut [SDH deficiency, n = 15 (45%), NF1, n = 10 (30%), BRAF, n = 1(3%), NF1&BRAF, n = 1 (3%)]. 5pts had quadruple wild type GIST. Most GISTs had at least one genetic alteration in a non-driver allele (74%, n = 141/191)[frequently mutated genes in KIT exon 11 driven i) primary tumors include TP53, MAX, MLL2, SETD2, PIK3CA, TSC1; and ii) metastatic tumors include RB1, SETD2, PTEN, ANKRD11, TP53, TSC1]. CDKN2A deletion was the most common copy number alteration identified in KIT driven GIST and occurred most often in metastatic samples (with and without co-occurring, secondary KIT muts) and those with high mitotic rate. Conclusions: NGS of GIST informs clinical management in the majority of pts through the identification of muts in canonical driver genes. NGS also identifies a high prevalence of tumor-specific genetic alterations in non-canonical driver genes. These genes function in multiple pathways including intracellular signaling, chromatin remodeling, proteasomal degradation and cell cycle regulation.

scholarly journals Next-Generation Sequencing Improves Diagnosis, Prognosis and Clinical Management of Myeloid Neoplasms

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1364 ◽  
Author(s):  
Diego Carbonell ◽  
Julia Suárez-González ◽  
María Chicano ◽  
Cristina Andrés-Zayas ◽  
Juan Carlos Triviño ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Copy Number Variants ◽  
Genetic Alterations ◽  
Next Generation ◽  
Pathogenic Variants ◽  
Myeloid Neoplasms ◽  
Diagnostic Samples ◽  
Gene Panels ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Molecular diagnosis of myeloid neoplasms (MN) is based on the detection of multiple genetic alterations using various techniques. Next-generation sequencing (NGS) has been proved as a useful method for analyzing many genes simultaneously. In this context, we analyzed diagnostic samples from 121 patients affected by MN and ten relapse samples from a subset of acute myeloid leukemia patients using two enrichment-capture NGS gene panels. Pathogenicity classification of variants was enhanced by the development and application of a custom onco-hematology score. A total of 278 pathogenic variants were detected in 84% of patients. For structural alterations, 82% of those identified by cytogenetics were detected by NGS, 25 of 31 copy number variants and three out of three translocations. The detection of variants using NGS changed the diagnosis of seven patients and the prognosis of 15 patients and enabled us to identify 44 suitable candidates for clinical trials. Regarding AML, six of the ten relapsed patients lost or gained variants, comparing with diagnostic samples. In conclusion, the use of NGS panels in MN improves genetic characterization of the disease compared with conventional methods, thus demonstrating its potential clinical utility in routine clinical testing. This approach leads to better-adjusted treatments for each patient.

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 MET amplification identified by next-generation sequencing and its clinical relevance for MET inhibitors

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Lun-Xi Peng ◽  
Guang-Ling Jie ◽  
An-Na Li ◽  
Si-Yang Liu ◽  
Hao Sun ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Copy Number ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Precision Oncology ◽  
Next Generation ◽  
Driver Genes ◽  
Generation Sequencing

Abstract Background MET amplification plays an important role in the development of non-small-cell lung cancer (NSCLC) either de novo or in resistance to epidermal growth factor receptor tyrosine–kinase inhibitor (EGFR-TKI) settings. Fluorescence in situ hybridization (FISH) is the standard method for MET amplification. With more and more discoveries of oncogenic driver genes, next-generation sequencing (NGS) plays a significant role in precision oncology. Meanwhile, the role of NGS in MET amplification remains uncertain. Methods Forty patients diagnosed with advanced NSCLC were included. FISH and NGS were conducted prior to MET inhibitors treatment. MET amplification by FISH was defined as a MET/CEP7 ratio of  >  2.0 and/or copy number (CN)  >  5. MET amplification by NGS was defined as gene copy number (GCN)  ≥  5. Results The concordance rate among FISH and NGS was 62.5% (25/40). MET amplification identified by FISH showed the optimal predictive value. The partial response (PR) rate was 68.0% (17/25 with MET amplification) vs. 6.7% (1/15 without MET amplification); the median progression-free survival (PFS) was 5.4 months versus 1.0 months (P  < 0.001). MET amplification identified by NGS failed to distinguish significant clinical outcomes. The PR rate was 60.0% (6/10, with MET GCN  ≥ 5) vs. 40.0% (12/30, with MET GCN  < 5); the median PFS was 4.8 months vs. 2.2 months (P  = 0.357). The PR rate was 68.8% (11/16) and the median PFS was 4.8 months in patients with focal amplification by NGS. Conclusions MET amplification identified by FISH remains the optimal biomarker to identify suitable candidates for MET-TKI therapy. In comparison, amplification identified by NGS seems not as robust to be effective predictive biomarker. Further exploration is needed regarding the focal amplification by NGS in predicting the efficacy.

scholarly journals Pan-cancer detection of driver genes at the single-patient resolution

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Joel Nulsen ◽  
Hrvoje Misetic ◽  
Christopher Yau ◽  
Francesca D. Ciccarelli
Keyword(s):  
False Positive Rate ◽  
Genetic Alterations ◽  
Therapeutic Interventions ◽  
Precision Oncology ◽  
Cancer Type ◽  
Rare Cancer ◽  
Driver Genes ◽  
Cancer Data ◽  
Cancer Types ◽  
Pan Cancer

Abstract Background Identifying the complete repertoire of genes that drive cancer in individual patients is crucial for precision oncology. Most established methods identify driver genes that are recurrently altered across patient cohorts. However, mapping these genes back to patients leaves a sizeable fraction with few or no drivers, hindering our understanding of cancer mechanisms and limiting the choice of therapeutic interventions. Results We present sysSVM2, a machine learning software that integrates cancer genetic alterations with gene systems-level properties to predict drivers in individual patients. Using simulated pan-cancer data, we optimise sysSVM2 for application to any cancer type. We benchmark its performance on real cancer data and validate its applicability to a rare cancer type with few known driver genes. We show that drivers predicted by sysSVM2 have a low false-positive rate, are stable and disrupt well-known cancer-related pathways. Conclusions sysSVM2 can be used to identify driver alterations in patients lacking sufficient canonical drivers or belonging to rare cancer types for which assembling a large enough cohort is challenging, furthering the goals of precision oncology. As resources for the community, we provide the code to implement sysSVM2 and the pre-trained models in all TCGA cancer types (https://github.com/ciccalab/sysSVM2).

scholarly journals TAZ-CAMTA1 and YAP-TFE3 modulate the basal TAZ/YAP transcriptional program by recruiting the ATAC histone acetyltransferase complex

2020 ◽  
Author(s):  
Nicole Merritt ◽  
Keith Garcia ◽  
Dushyandi Rajendran ◽  
Zhen-Yuan Lin ◽  
Xiaomeng Zhang ◽  
...  
Keyword(s):  
Fusion Proteins ◽  
Histone Acetyltransferase ◽  
Genetic Alterations ◽  
Epithelioid Hemangioendothelioma ◽  
Complex Interaction ◽  
Gene Fusions ◽  
Transcriptional Program ◽  
Epigenetic Modifiers ◽  
Oncogenic Driver ◽  
Generation Sequencing

AbstractEpithelioid hemangioendothelioma (EHE) is a vascular sarcoma that metastasizes early and lacks an effective medical therapy. The TAZ-CAMTA1 and YAP-TFE3 fusion proteins are chimeric transcription factors and initiating oncogenic drivers of EHE. A combined proteomic/genetic screen identified YEATS2 and ZZZ3, components of the Ada2a-containing histone acetyltransferase (ATAC) complex, as key interactors of both TAZ-CAMTA1 and YAP-TFE3 despite the dissimilarity of the C terminal fusion partners CAMTA1 and TFE3. An integrative next generation sequencing approach showed the fusion proteins drive expression of a unique transcriptome distinct from TAZ and YAP by simultaneously hyperactivating a TEAD-based transcriptional program and modulating the chromatin environment via interaction with the ATAC complex. Interaction of the ATAC complex with both TAZ-CAMTA1 and YAP-TFE3 indicates the histone acetyltransferase complex is an oncogenic driver in EHE and potentially other sarcomas. Furthermore, the ATAC complex is an enzymatic transcriptional cofactor required for both fusion proteins in EHE, representing a unifying therapeutic target for this sarcoma. Gene fusions are the most common genetic alterations activating TAZ and YAP in cancer, and this study serves as a template for identifying epigenetic modifiers recruited by the C terminal fusion partners of other TAZ/YAP gene fusions occurring in gliomas, carcinomas, and other sarcomas.SummaryTAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptional program by recruiting the ATAC complex and modifying the chromatin landscape.

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