Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE): A Cloud-based Platform for Curating and Classifying Germline Variants

Edmonson, Michael N.; Patel, Aman; Hedges, Dale J.; Wang, Zhaoming; Rampersaud, Evadnie; Kesserwan, Chimene; Zhou, Xin; Liu, Yanling; Newman, Scott; Rusch, Michael; McLeod, Clay; Wilkinson, Mark R.; Rice, Stephen V.; Becksfort, Jared; Nichols, Kim E.; Robison, Leslie L.; Downing, James R.; Zhang, Jinghui

doi:10.1101/340901

Cited by 3 publications

(5 citation statements)

References 49 publications

(41 reference statements)

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“…Twelve hundred genes known to play a role in the pathogenesis of cancer were interrogated using tumor genomic data. Genes were considered in the context of each patient's tumor type and prioritized for review, as previously described (19). Given the potential effects of structural events and gene fusions on protein expression and function, we reported novel events if there was strong sequence support and the structural event or gene fusion involved genes of potential relevance to cancer.…”

Section: Overview Of Somatic Alterationsmentioning

confidence: 99%

“…WGS, WES and RNA-Seq data were aligned and variants called and annotated using previously published algorithms (19,33,69,70) and automated pipeline infrastructure (14).…”

Section: Variant Classification and Reportingmentioning

confidence: 99%

“…Sequence variants were called using Bambino(69), DNA SVs using CREST(70), RNA SVs including ITD using CICERO(78), a local assembly-based algorithm that integrates RNA-seq read support with extensive annotation for candidate ranking and available online at: https://www.stjude.cloud/tools/rapid_RNA-Seq), and CNVs and allelic imbalance with CONSERTING (33). Variants were annotated using the Medal Ceremony/PeCanPIE pipeline (19) (available online at: https://pecan.stjude.cloud/pie). We estimated TMB by counting all exonic and UTR variants that passed manual review by a genome analyst in addition to high-quality intronic and non-coding somatic variants falling outside of repeat regions.…”

Section: Bioinformatics Analysismentioning

confidence: 99%

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Genomes for Kids: The Scope of Pathogenic Mutations in Pediatric Cancer Revealed by Comprehensive DNA and RNA Sequencing

et al. 2021

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Genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. Here, we used a three-platform sequencing approach, including whole genome (WGS), exome, and RNA sequencing, to examine tumor and germline genomes from 309 prospectively identified children with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type. Eighty-six percent of patients harbored diagnostic (53%), prognostic (57%), therapeutically-relevant (25%), and/or cancer predisposing (18%) variants. Inclusion of WGS enabled detection of activating gene fusions and enhancer hijacks (36% and 8% of tumors, respectively), small intragenic deletions (15% of tumors) and mutational signatures revealing of pathogenic variant effects. Evaluation of paired tumor-normal data revealed relevance to tumor development for 55% of pathogenic germline variants. This study demonstrates the power of a three-platform approach that incorporates WGS to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers. STATEMENT OF SIGNIFICANCEPediatric cancers are driven by diverse genomic lesions and sequencing has proven useful in evaluating high risk and relapsed/refractory cases. We show that combined whole genome, exome, and RNA-sequencing of tumor and paired normal tissues enables identification and characterization of genetic drivers across the full spectrum of pediatric cancers.Research.

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Section: Overview Of Somatic Alterationsmentioning

confidence: 99%

“…WGS, WES and RNA-Seq data were aligned and variants called and annotated using previously published algorithms (19,33,69,70) and automated pipeline infrastructure (14).…”

Section: Variant Classification and Reportingmentioning

confidence: 99%

Section: Bioinformatics Analysismentioning

confidence: 99%

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Genomes for Kids: The Scope of Pathogenic Mutations in Pediatric Cancer Revealed by Comprehensive DNA and RNA Sequencing

et al. 2021

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“…9418 variants were downloaded from cBioportal (July 15, 2021; Tables S11 and S12). We first analyzed putative pathogenicity of these variants by using PeCanPIE/MedalCeremony (Edmonson et al, 2019), and compared the pathogenicity classification with the ''Driver'' status provided by cBioportal. We found that gene ARID2 has substantial under calling of pathogenicity by cBioportal (15 variants called as driver mutations by CBioportal versus 214 additional variants called as pathogenic/likely pathogenic by PeCanPIE/MedalCeremony).…”

Section: Declaration Of Interestsmentioning

confidence: 99%

NSD1 mediates antagonism between SWI/SNF and polycomb complexes and is required for transcriptional activation upon EZH2 inhibition

Drosos¹,

Myers²,

Xu³

et al. 2022

Molecular Cell

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“…(4) < 10 depth in normal samples; (5) identification as variants in the 1000 Genome East Asian Project (August 2015 release) and not in the COSMIC database (version 70); and (6) identification as variants in the ExAC nonTCGA East Asian database (version 0.3) and not in the COSMIC database. We used Medal Ceremony [27] to annotate driver sites. All the variants were verified by the Integrative Genomics Viewer [28].…”

Section: Whole-exome Sequencing Data Analysismentioning

confidence: 99%

Integrated Genomic Analyses Identify High-Risk Factors and Actionable Targets in T-Cell Acute Lymphoblastic Leukemia

Zhu

Dong

Zhang

et al. 2021

Preprint

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T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy often associated with poor outcomes. Recent unbiased genomic landscape studies have identified frequently mutated genes and dysregulated pathways in major subtypes of T-ALLs. However, few of these large-scaled genomic analyses have survival-related data, which makes molecular-based prognosis and designing new-targeted therapies difficult. To identify high-risk factors and potential actionable targets for T-ALL, we perform integrated genomic and transcriptomic analyses on samples from 165 Chinese pediatric and adult T-ALL patients, of whom 85% have outcome information. Among 47 recurrently mutated genes in 7 functional categories, we identify RAS and PI3K pathway mutations as poor survival factors for non-TAL and TAL subtypes, respectively. Mutations in the PI3K pathway are mutually exclusive with mutations in the RAS and NOTCH1 pathways, and transcription factors. Further analysis demonstrates that approximately 43% of the high-risk patients harbor at least one potential actionable alteration identified in this study, and T-ALLs with RAS pathway mutations are hypersensitive to MEKi in vitro and in vivo. Thus, our integrated genomic analyses not only systematically identify high-risk factors but suggest that these high-risk factors are promising targets for T-ALL therapies.

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Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE): A Cloud-based Platform for Curating and Classifying Germline Variants

Abstract: 8Variant interpretation in the era of next-generation sequencing (NGS) is challenging. While 1 9

Cited by 3 publications

References 49 publications

Genomes for Kids: The Scope of Pathogenic Mutations in Pediatric Cancer Revealed by Comprehensive DNA and RNA Sequencing

Genomes for Kids: The Scope of Pathogenic Mutations in Pediatric Cancer Revealed by Comprehensive DNA and RNA Sequencing

NSD1 mediates antagonism between SWI/SNF and polycomb complexes and is required for transcriptional activation upon EZH2 inhibition

Integrated Genomic Analyses Identify High-Risk Factors and Actionable Targets in T-Cell Acute Lymphoblastic Leukemia

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