Publications by authors named "Olena Morozova Vaske"

7 Publications

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Hydra: A mixture modeling framework for subtyping pediatric cancer cohorts using multimodal gene expression signatures.

PLoS Comput Biol 2020 04 10;16(4):e1007753. Epub 2020 Apr 10.

Genomics Institute, University of California, Santa Cruz, Santa Cruz, California, United States of America.

Precision oncology has primarily relied on coding mutations as biomarkers of response to therapies. While transcriptome analysis can provide valuable information, incorporation into workflows has been difficult. For example, the relative rather than absolute gene expression level needs to be considered, requiring differential expression analysis across samples. However, expression programs related to the cell-of-origin and tumor microenvironment effects confound the search for cancer-specific expression changes. To address these challenges, we developed an unsupervised clustering approach for discovering differential pathway expression within cancer cohorts using gene expression measurements. The hydra approach uses a Dirichlet process mixture model to automatically detect multimodally distributed genes and expression signatures without the need for matched normal tissue. We demonstrate that the hydra approach is more sensitive than widely-used gene set enrichment approaches for detecting multimodal expression signatures. Application of the hydra analysis framework to small blue round cell tumors (including rhabdomyosarcoma, synovial sarcoma, neuroblastoma, Ewing sarcoma, and osteosarcoma) identified expression signatures associated with changes in the tumor microenvironment. The hydra approach also identified an association between ATRX deletions and elevated immune marker expression in high-risk neuroblastoma. Notably, hydra analysis of all small blue round cell tumors revealed similar subtypes, characterized by changes to infiltrating immune and stromal expression signatures.
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http://dx.doi.org/10.1371/journal.pcbi.1007753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176284PMC
April 2020

Erratum: Data sharing for clinical utility.

Cold Spring Harb Mol Case Stud 2019 Dec 13;5(6). Epub 2019 Dec 13.

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http://dx.doi.org/10.1101/mcs.a004929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913145PMC
December 2019

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Cell Rep 2019 11;29(6):1675-1689.e9

Division of Oncology, Children's Hospital of Philadelphia, and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-4318, USA. Electronic address:

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer.
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http://dx.doi.org/10.1016/j.celrep.2019.09.071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880934PMC
November 2019

Data sharing for clinical utility.

Cold Spring Harb Mol Case Stud 2019 10 23;5(5). Epub 2019 Oct 23.

University of California Santa Cruz Genomics Institute, Santa Cruz, California 95064, USA.

Genomic data offer valuable insights that can be used to help find treatments and cures for disease. Precision medicine, defined by the NIH as "an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person," is gaining acceptance among physicians, who are beginning to integrate patient-centric data analysis into clinical decision-making. Although precision medicine makes use of various types of data, this piece focuses on molecular characterization data specifically, as the discoveries yielded from these data can advance thinking around clinical care for cancer patients. Our pediatrics genomics team at the University of California Santa Cruz Genomics Institute is uniquely situated to discuss the use of shared genomic data for clinical benefit because our collaborations with hospital partners in the United States and internationally rely on big-data comparative genomic analysis. Using shared data, Treehouse Childhood Cancer Initiative develops methods for comparative analysis of tumor RNA sequencing profiles from single patients for the purposes of identifying overexpressed oncogenes that could be targeted by therapies in the clinic. To enable and improve this analysis, we continuously increase the size of our data compendium by adding public pediatric tumor RNA sequencing data sets. We developed an approach for assessing the quality of shared RNA sequencing data to ensure the integrity of the data. In this approach we calculate the number of mapped exonic nonduplicate (MEND) reads, applying a 10 million MEND read minimum threshold for inclusion in our comparative analysis. In collaboration with Stanford University and Lucile Packard Children's Hospital Stanford, our team at Treehouse Childhood Cancer Initiative explores the value to researchers everywhere of shared genomic data for clinical utility and the challenges of data sharing that threaten to impede otherwise rapid advances in precision medicine. This Perspective offers recommendations for maximizing the use of genomic data to make discoveries that will benefit patients.
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http://dx.doi.org/10.1101/mcs.a004689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824251PMC
October 2019

Barriers to accessing public cancer genomic data.

Sci Data 2019 06 20;6(1):98. Epub 2019 Jun 20.

UC Santa Cruz, 1156 High Street, Mailstop: Genomics Institute, Santa Cruz, CA, 95064, USA.

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http://dx.doi.org/10.1038/s41597-019-0096-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586850PMC
June 2019

Identification of Novel RAS Signaling Therapeutic Vulnerabilities in Diffuse Intrinsic Pontine Gliomas.

Cancer Res 2019 08 14;79(16):4026-4041. Epub 2019 Jun 14.

John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.

Diffuse intrinsic pontine gliomas (DIPG) are incurable brain tumors with an aggressive onset. Apart from irradiation, there are currently no effective therapies available for patients with DIPG, who have a median survival time of less than one year. Most DIPG cells harbor mutations in genes encoding histone H3 (H3K27M) proteins, resulting in a global reduction of H3K27 trimethylation and activation of oncogenic signaling pathways. Here we show that the H3K27M mutations contribute to RAS pathway signaling, which is augmented by additional RAS activators including PDGFRA. H3K27M mutation led to increased expression of receptor tyrosine kinases (RTK). A RAS pathway functional screen identified ERK5, but not ERK1/2, as a RAS pathway effector important for DIPG growth. Suppression of ERK5 decreased DIPG cell proliferation and induced apoptosis and . In addition, depletion or inhibition of ERK5 significantly increased survival of mice intracranially engrafted with DIPG cells. Mechanistically, ERK5 directly stabilized the proto-oncogene MYC at the protein level. Collectively, our data demonstrate an underappreciated role of H3K27M in RAS activation and reveal novel therapeutic targets for treating DIPG tumors. SIGNIFICANCE: These findings identify the H3K27M mutation as an enhancer of RAS activation in DIPG and ERK5 as a novel, immediately actionable molecular target. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/16/4026/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3521DOI Listing
August 2019

Data sharing for pediatric cancers.

Science 2019 03;363(6432):1125

David Haussler is a Distinguished Professor in the Genomics Institute, in the Department of Biomolecular Engineering, and in the Howard Hughes Medical Institute at the University of California, Santa Cruz, Santa Cruz, CA, USA.

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http://dx.doi.org/10.1126/science.aax2739DOI Listing
March 2019