Abstract:
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.
journal_name
BMC Med Genomicsjournal_title
BMC medical genomicsauthors
Cheng L,Pandya PH,Liu E,Chandra P,Wang L,Murray ME,Carter J,Ferguson M,Saadatzadeh MR,Bijangi-Visheshsaraei K,Marshall M,Li L,Pollok KE,Renbarger JLdoi
10.1186/s12920-018-0456-5subject
Has Abstractpub_date
2019-01-31 00:00:00pages
23issue
Suppl 1issn
1755-8794pii
10.1186/s12920-018-0456-5journal_volume
12pub_type
杂志文章abstract:BACKGROUND:Integrating multiple data sources is indispensable in improving disease gene identification. It is not only due to the fact that disease genes associated with similar genetic diseases tend to lie close with each other in various biological networks, but also due to the fact that gene-disease associations are...
journal_title:BMC medical genomics
pub_type: 杂志文章
doi:10.1186/1755-8794-8-S3-S2
更新日期:2015-01-01 00:00:00
abstract:BACKGROUND:Cancer shows a great diversity in its clinical behavior which cannot be easily predicted using the currently available clinical or pathological markers. The identification of pathways associated with lymph node metastasis (N+) and recurrent head and neck squamous cell carcinoma (HNSCC) may increase our under...
journal_title:BMC medical genomics
pub_type: 杂志文章
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更新日期:2011-04-13 00:00:00
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更新日期:2019-12-27 00:00:00
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journal_title:BMC medical genomics
pub_type: 杂志文章
doi:10.1186/1755-8794-6-20
更新日期:2013-06-10 00:00:00
abstract:BACKGROUND:Preterm birth (PTB), defined as infant delivery before 37 weeks of completed gestation, results from the interaction of both genetic and environmental components and constitutes a complex multifactorial syndrome. Transcriptome analysis of PTB has proven challenging because of the multiple causes of PTB and t...
journal_title:BMC medical genomics
pub_type: 杂志文章
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更新日期:2019-04-01 00:00:00
abstract:BACKGROUND:Postmenopausal hormone therapy (HT) influences endogenous hormone concentrations and increases the risk of breast cancer. Gene expression profiling may reveal the mechanisms behind this relationship.Our objective was to explore potential associations between sex hormones and gene expression in whole blood fr...
journal_title:BMC medical genomics
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doi:10.1186/1755-8794-4-29
更新日期:2011-03-31 00:00:00
abstract:BACKGROUND:Bladder cancer has numerous genomic features that are potentially actionable by targeted agents. Nevertheless, both pre-clinical and clinical research using molecular targeted agents have been very limited in bladder cancer. RESULTS:We created the Genomics of Drug Sensitivity in Bladder Cancer (GDBC) databa...
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journal_title:BMC medical genomics
pub_type: 杂志文章
doi:10.1186/1755-8794-1-46
更新日期:2008-09-30 00:00:00
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pub_type: 杂志文章
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更新日期:2012-06-18 00:00:00
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journal_title:BMC medical genomics
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更新日期:2018-08-08 00:00:00
abstract::Sickle cell disease and β thalassemia are common severe diseases with little effective pathophysiologically-based treatment. Their phenotypic heterogeneity prompted genomic approaches to identify modifiers that ultimately might be exploited therapeutically. Fetal hemoglobin (HbF) is the major modulator of the phenotyp...
journal_title:BMC medical genomics
pub_type: 杂志文章,评审
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更新日期:2015-07-29 00:00:00
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更新日期:2014-06-17 00:00:00
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更新日期:2018-11-20 00:00:00
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更新日期:2008-09-29 00:00:00
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更新日期:2015-05-21 00:00:00
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journal_title:BMC medical genomics
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