Abstract 445: Integrated proteogenomic characterization across seven histological types of pediatric brain tumors

Petralia, Francesca; Tignor, Nicole; Reva, Boris; Raman, Pichai; Chowdhury, Shrabanti; Rykunov, Dmitry; Krek, Azra; Ma, Wanli; Ji, Jiayi; Song, Xiaoyu; Zhu, Yuankun; Rokita, Jo Lynne; Colaprico, Antonio; Calinawan, Anna; Whiteaker, Jeffrey R.; Ivey, Richard G.; Gümüş, Zeynep H.; Kalayci, Selim; Garcia, Gonzalo Lopez; Yoo, Seungyeul; Katsnelson, Lizabeth; Wang, Ying; Kennedy, Jacob J.; Voytovich, Uliana J.; Zhao, Lei; Leprevost, Felipe da Veiga; Chang, Hui-Yin; Gaonkar, Krutika S.; Appert, Elizabeth; Cuellar, Ximena P.; Lilly, Jena; Zhu, Jun; Schadt, Eric E.; Mesri, Medhi; Boja, Emily S.; Hiltka, Tara; Rodriguez, Henry; Ding, Li; Iavarone, Antonio; Wiznerowicz, Maciej; Nesvizhskii, Alexey I.; Fenyö, David; Gygi, Steven P.; Paulovich, Amanda G.; Resnick, Adam; Storm, Phillip B.; Rood, Brian R.; Wang, Pei

doi:10.1158/1538-7445.am2020-445

Cited by 17 publications

(37 citation statements)

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“…Ryall et al 17 described rare KIAA1549::BRAF fusion breakpoints (15:11) in two infants with disseminated pLGG who had poor outcomes. Our study builds on this by showing that rare/novel KIAA1549::BRAF fusion breakpoints, including 15:11, are highly enriched in recurrent/progressive pLGGs within PNOC001 and external cohorts 44,45 and predict worse clinical outcomes in PNOC001. We found these breakpoints enriched in young patients (younger than 3 years) and patients with a supratentorial midline PA.…”

Section: Discussionmentioning

confidence: 67%

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Everolimus for Children With Recurrent or Progressive Low-Grade Glioma: Results From the Phase II PNOC001 Trial

Haas-Kogan,

Aboian,

Minturn

et al. 2024

JCO

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PURPOSE The PNOC001 phase II single-arm trial sought to estimate progression-free survival (PFS) associated with everolimus therapy for progressive/recurrent pediatric low-grade glioma (pLGG) on the basis of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway activation as measured by phosphorylated-ribosomal protein S6 and to identify prognostic and predictive biomarkers. PATIENTS AND METHODS Patients, age 3-21 years, with progressive/recurrent pLGG received everolimus orally, 5 mg/m2 once daily. Frequency of driver gene alterations was compared among independent pLGG cohorts of newly diagnosed and progressive/recurrent patients. PFS at 6 months (primary end point) and median PFS (secondary end point) were estimated for association with everolimus therapy. RESULTS Between 2012 and 2019, 65 subjects with progressive/recurrent pLGG (median age, 9.6 years; range, 3.0-19.9; 46% female) were enrolled, with a median follow-up of 57.5 months. The 6-month PFS was 67.4% (95% CI, 60.0 to 80.0) and median PFS was 11.1 months (95% CI, 7.6 to 19.8). Hypertriglyceridemia was the most common grade ≥3 adverse event. PI3K/AKT/mTOR pathway activation did not correlate with clinical outcomes (6-month PFS, active 68.4% v nonactive 63.3%; median PFS, active 11.2 months v nonactive 11.1 months; P = .80). Rare/novel KIAA1549::BRAF fusion breakpoints were most frequent in supratentorial midline pilocytic astrocytomas, in patients with progressive/recurrent disease, and correlated with poor clinical outcomes (median PFS, rare/novel KIAA1549::BRAF fusion breakpoints 6.1 months v common KIAA1549::BRAF fusion breakpoints 16.7 months; P < .05). Multivariate analysis confirmed their independent risk factor status for disease progression in PNOC001 and other, independent cohorts. Additionally, rare pathogenic germline variants in homologous recombination genes were identified in 6.8% of PNOC001 patients. CONCLUSION Everolimus is a well-tolerated therapy for progressive/recurrent pLGGs. Rare/novel KIAA1549::BRAF fusion breakpoints may define biomarkers for progressive disease and should be assessed in future clinical trials.

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Section: Discussionmentioning

confidence: 67%

“…Our study builds on this by showing that rare/novel KIAA1549:: BRAF fusion breakpoints, including 15:11, are highly enriched in recurrent/progressive pLGGs within PNOC001 and external cohorts 44,45 and predict worse clinical outcomes in PNOC001.…”

Section: Discussionmentioning

confidence: 68%

Everolimus for Children With Recurrent or Progressive Low-Grade Glioma: Results From the Phase II PNOC001 Trial

Haas-Kogan,

Aboian,

Minturn

et al. 2024

JCO

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“…The Clinical Proteomic Tumor Analysis Consortium (CPTAC) has reported a range of tumor-tissue studies that are not necessarily HT but have sample sizes larger than 100 [128][129][130][131][132][133][134][135][136] and are thus worth mentioning in this review. These studies focus on proteogenomic analysis, identifying cancer-relevant pathways or potential therapeutic targets.…”

Section: Applications Of Ht Proteomics In Biomedical Studiesmentioning

confidence: 99%

Mass spectrometry‐based high‐throughput proteomics and its role in biomedical studies and systems biology

et al. 2022

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There are multiple reasons why the next generation of biological and medical studies require increasing numbers of samples. Biological systems are dynamic, and the effect of a perturbation depends on the genetic background and environment. As a consequence, many conditions need to be considered to reach generalizable conclusions. Moreover, human population and clinical studies only reach sufficient statistical power if conducted at scale and with precise measurement methods. Finally, many proteins remain without sufficient functional annotations, because they have not been systematically studied under a broad range of conditions. In this review, we discuss the latest technical developments in mass spectrometry (MS)-based proteomics that facilitate large-scale studies by fast and efficient chromatography, fast scanning mass spectrometers, data-independent acquisition (DIA), and new software. We further highlight recent studies which demonstrate how high-throughput (HT) proteomics can be applied to capture biological diversity, to annotate gene functions or to generate predictive and prognostic models for human diseases.

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“…They are poorly represented by gene expressions as proteins employee complex, multi-level post translational modification that are not reflected at the mRNA level. Studies that quantified both mRNA gene expressions and proteomic abundances identified a median correlation of <0.5 in lung [5] and many other tissues [6, 7]. Therefore, identifying and validating genes and pathways at protein level that are associated with ACE2 is crucial for further understanding the roles of this gene in coronavirus infection.…”

Section: Introductionmentioning

confidence: 99%

“…The second group focuses on associations by leveraging pre-estimated cell-type composition for cell-type controlled or specific effects. For example, cell-type composition estimates are often treated as covariates in simple association analysis for “unconfounded” effects [6, 7]. Cell-type specific associations are also considered by modeling interactive effects between the estimated cell-type composition and covariates [26] or by considering hierarchical mixture models to decompose the observed tissue-level traits into their values in different cell types for their cell-type specific associations [27].…”

Section: Introductionmentioning

confidence: 99%

iProMix: A decomposition model for studying the function of ACE2 based on bulk proteogenomic data for coronavirus pathogenesis

Song

Wang

2021

Preprint

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Both SARS-CoV and SARS-CoV-2 use ACE2 receptors to enter epithelial cells in lung and many other tissues to cause human diseases. Genes and pathways that regulate ACE2 may facilitate/inhibit viral entry and replication, and genes and pathways that are controlled by ACE2 may be perturbed during infection, both affecting disease severity and outcomes. It is critical to understand how genes and pathways are associated with ACE2 in epithelial cells by leveraging proteomic data, but an accurate large-scale proteomic profiling at cellular resolution is not feasible at current stage. Therefore, we propose iProMix, a novel framework that decomposes bulk tissue proteomic data to identify epithelial cell component specific associations between ACE2 and other proteins. Unlike existing decomposition based association analyses, iProMix allows both predictors and outcomes to be impacted by cell type composition of the tissue and accounts for the impacts of decomposition variations and errors on hypothesis tests. It also builds in the functions to improve cell type estimation if estimates from existing literature are unsatisfactory. Simulations demonstrated that iProMix has well-controlled false discovery rate and large power in non-asymptotic settings with both correctly and mis-specified cell-type composition. We applied iProMix to the 110 adjacent normal tissue samples of patients with lung adenocarcinoma from Clinical Proteomic Tumor Analysis Consortium, and identified that interferon α and γ pathways were most significantly associated with ACE2 protein abundances in epithelial cells. Interestingly, the associations were sex-specific that the positive associations were only observed in men, while in women the associations were negative.

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Abstract 445: Integrated proteogenomic characterization across seven histological types of pediatric brain tumors

Cited by 17 publications

References 0 publications

Everolimus for Children With Recurrent or Progressive Low-Grade Glioma: Results From the Phase II PNOC001 Trial

Everolimus for Children With Recurrent or Progressive Low-Grade Glioma: Results From the Phase II PNOC001 Trial

Mass spectrometry‐based high‐throughput proteomics and its role in biomedical studies and systems biology

iProMix: A decomposition model for studying the function of ACE2 based on bulk proteogenomic data for coronavirus pathogenesis

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