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Integration of genomic copy number variations and chemotherapy-response biomarkers in pediatric sarcoma

BACKGROUND: While most pediatric sarcomas respond to front-line therapy, some bone sarcomas do not show radiographic response like soft-tissue sarcomas (rhabdomyosarccomas) but do show 90% necrosis. Though, new therapies are urgently needed to improve survival and quality of life in pediatric patien...

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Autores principales: Cheng, Lijun, Pandya, Pankita H., Liu, Enze, Chandra, Pooja, Wang, Limei, Murray, Mary E., Carter, Jacquelyn, Ferguson, Michael, Saadatzadeh, Mohammad Reza, Bijangi-Visheshsaraei, Khadijeh, Marshall, Mark, Li, Lang, Pollok, Karen E., Renbarger, Jamie L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357363/
https://www.ncbi.nlm.nih.gov/pubmed/30704460
http://dx.doi.org/10.1186/s12920-018-0456-5
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author Cheng, Lijun
Pandya, Pankita H.
Liu, Enze
Chandra, Pooja
Wang, Limei
Murray, Mary E.
Carter, Jacquelyn
Ferguson, Michael
Saadatzadeh, Mohammad Reza
Bijangi-Visheshsaraei, Khadijeh
Marshall, Mark
Li, Lang
Pollok, Karen E.
Renbarger, Jamie L.
author_facet Cheng, Lijun
Pandya, Pankita H.
Liu, Enze
Chandra, Pooja
Wang, Limei
Murray, Mary E.
Carter, Jacquelyn
Ferguson, Michael
Saadatzadeh, Mohammad Reza
Bijangi-Visheshsaraei, Khadijeh
Marshall, Mark
Li, Lang
Pollok, Karen E.
Renbarger, Jamie L.
author_sort Cheng, Lijun
collection PubMed
description BACKGROUND: While most pediatric sarcomas respond to front-line therapy, some bone sarcomas do not show radiographic response like soft-tissue sarcomas (rhabdomyosarccomas) but do show 90% necrosis. Though, new therapies are urgently needed to improve survival and quality of life in pediatric patients with sarcomas. Complex chromosomal aberrations such as amplifications and deletions of DNA sequences are frequently observed in pediatric sarcomas. Evaluation of copy number variations (CNVs) associated with pediatric sarcoma patients at the time of diagnosis or following therapy offers an opportunity to assess dysregulated molecular targets and signaling pathways that may drive sarcoma development, progression, or relapse. The objective of this study was to utilize publicly available data sets to identify potential predictive biomarkers of chemotherapeutic response in pediatric Osteosarcoma (OS), Rhabdomyosarcoma (RMS) and Ewing’s Sarcoma Family of Tumors (ESFTs) based on CNVs following chemotherapy (OS n = 117, RMS n = 64, ESFTs n = 25 tumor biopsies). METHODS: There were 206 CNV profiles derived from pediatric sarcoma biopsies collected from the public databases TARGET and NCBI-Gene Expression Omnibus (GEO). Through our comparative genomic analyses of OS, RMS, and ESFTs and 22,255 healthy individuals called from the Database of Genomic Variants (DGV), we identified CNVs (amplifications and deletions) pattern of genomic instability in these pediatric sarcomas. By integrating CNVs of Cancer Cell Line Encyclopedia (CCLE) identified in the pool of genes with drug-response data from sarcoma cell lines (n = 27) from Cancer Therapeutics Response Portal (CTRP) Version 2, potential predictive biomarkers of therapeutic response were identified. RESULTS: Genes associated with survival and/recurrence of these sarcomas with statistical significance were found on long arm of chromosome 8 and smaller aberrations were also identified at chromosomes 1q, 12q and x in OS, RMS, and ESFTs. A pool of 63 genes that harbored amplifications and/or deletions were frequently associated with recurrence across OS, RMS, and ESFTs. Correlation analysis of CNVs from CCLE with drug-response data of CTRP in 27 sarcoma cell lines, 33 CNVs out of 63 genes correlated with either sensitivity or resistance to 17 chemotherapies from which actionable CNV signatures such as IGF1R, MYC, MAPK1, ATF1, and MDM2 were identified. These CNV signatures could potentially be used to delineate patient populations that will respond versus those that will not respond to a particular chemotherapy. CONCLUSIONS: The large-scale analyses of CNV-drug screening provides a platform to evaluate genetic alterations across aggressive pediatric sarcomas. Additionally, this study provides novel insights into the potential utilization of CNVs as not only prognostic but also as predictive biomarkers of therapeutic response. Information obtained in this study may help guide and prioritize patient-specific therapeutic options in pediatric bone and soft-tissue sarcomas. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12920-018-0456-5) contains supplementary material, which is available to authorized users.
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spelling pubmed-63573632019-02-07 Integration of genomic copy number variations and chemotherapy-response biomarkers in pediatric sarcoma Cheng, Lijun Pandya, Pankita H. Liu, Enze Chandra, Pooja Wang, Limei Murray, Mary E. Carter, Jacquelyn Ferguson, Michael Saadatzadeh, Mohammad Reza Bijangi-Visheshsaraei, Khadijeh Marshall, Mark Li, Lang Pollok, Karen E. Renbarger, Jamie L. BMC Med Genomics Research BACKGROUND: While most pediatric sarcomas respond to front-line therapy, some bone sarcomas do not show radiographic response like soft-tissue sarcomas (rhabdomyosarccomas) but do show 90% necrosis. Though, new therapies are urgently needed to improve survival and quality of life in pediatric patients with sarcomas. Complex chromosomal aberrations such as amplifications and deletions of DNA sequences are frequently observed in pediatric sarcomas. Evaluation of copy number variations (CNVs) associated with pediatric sarcoma patients at the time of diagnosis or following therapy offers an opportunity to assess dysregulated molecular targets and signaling pathways that may drive sarcoma development, progression, or relapse. The objective of this study was to utilize publicly available data sets to identify potential predictive biomarkers of chemotherapeutic response in pediatric Osteosarcoma (OS), Rhabdomyosarcoma (RMS) and Ewing’s Sarcoma Family of Tumors (ESFTs) based on CNVs following chemotherapy (OS n = 117, RMS n = 64, ESFTs n = 25 tumor biopsies). METHODS: There were 206 CNV profiles derived from pediatric sarcoma biopsies collected from the public databases TARGET and NCBI-Gene Expression Omnibus (GEO). Through our comparative genomic analyses of OS, RMS, and ESFTs and 22,255 healthy individuals called from the Database of Genomic Variants (DGV), we identified CNVs (amplifications and deletions) pattern of genomic instability in these pediatric sarcomas. By integrating CNVs of Cancer Cell Line Encyclopedia (CCLE) identified in the pool of genes with drug-response data from sarcoma cell lines (n = 27) from Cancer Therapeutics Response Portal (CTRP) Version 2, potential predictive biomarkers of therapeutic response were identified. RESULTS: Genes associated with survival and/recurrence of these sarcomas with statistical significance were found on long arm of chromosome 8 and smaller aberrations were also identified at chromosomes 1q, 12q and x in OS, RMS, and ESFTs. A pool of 63 genes that harbored amplifications and/or deletions were frequently associated with recurrence across OS, RMS, and ESFTs. Correlation analysis of CNVs from CCLE with drug-response data of CTRP in 27 sarcoma cell lines, 33 CNVs out of 63 genes correlated with either sensitivity or resistance to 17 chemotherapies from which actionable CNV signatures such as IGF1R, MYC, MAPK1, ATF1, and MDM2 were identified. These CNV signatures could potentially be used to delineate patient populations that will respond versus those that will not respond to a particular chemotherapy. CONCLUSIONS: The large-scale analyses of CNV-drug screening provides a platform to evaluate genetic alterations across aggressive pediatric sarcomas. Additionally, this study provides novel insights into the potential utilization of CNVs as not only prognostic but also as predictive biomarkers of therapeutic response. Information obtained in this study may help guide and prioritize patient-specific therapeutic options in pediatric bone and soft-tissue sarcomas. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12920-018-0456-5) contains supplementary material, which is available to authorized users. BioMed Central 2019-01-31 /pmc/articles/PMC6357363/ /pubmed/30704460 http://dx.doi.org/10.1186/s12920-018-0456-5 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Cheng, Lijun
Pandya, Pankita H.
Liu, Enze
Chandra, Pooja
Wang, Limei
Murray, Mary E.
Carter, Jacquelyn
Ferguson, Michael
Saadatzadeh, Mohammad Reza
Bijangi-Visheshsaraei, Khadijeh
Marshall, Mark
Li, Lang
Pollok, Karen E.
Renbarger, Jamie L.
Integration of genomic copy number variations and chemotherapy-response biomarkers in pediatric sarcoma
title Integration of genomic copy number variations and chemotherapy-response biomarkers in pediatric sarcoma
title_full Integration of genomic copy number variations and chemotherapy-response biomarkers in pediatric sarcoma
title_fullStr Integration of genomic copy number variations and chemotherapy-response biomarkers in pediatric sarcoma
title_full_unstemmed Integration of genomic copy number variations and chemotherapy-response biomarkers in pediatric sarcoma
title_short Integration of genomic copy number variations and chemotherapy-response biomarkers in pediatric sarcoma
title_sort integration of genomic copy number variations and chemotherapy-response biomarkers in pediatric sarcoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357363/
https://www.ncbi.nlm.nih.gov/pubmed/30704460
http://dx.doi.org/10.1186/s12920-018-0456-5
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