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Genome and transcriptome profiling of fibrolamellar hepatocellular carcinoma demonstrates p53 and IGF2BP1 dysregulation

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of HCC that most frequently affects young adults. Because of its rarity and an absence of preclinical models, our understanding of FL-HCC is limited. Our objective was to analyze chromosomal alterations and dysregulated gene expressio...

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Autores principales: Sorenson, Eric C., Khanin, Raya, Bamboat, Zubin M., Cavnar, Michael J., Kim, Teresa S., Sadot, Eran, Zeng, Shan, Greer, Jonathan B., Seifert, Adrian M., Cohen, Noah A., Crawley, Megan H., Green, Benjamin L., Klimstra, David S., DeMatteo, Ronald P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423588/
https://www.ncbi.nlm.nih.gov/pubmed/28486549
http://dx.doi.org/10.1371/journal.pone.0176562
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author Sorenson, Eric C.
Khanin, Raya
Bamboat, Zubin M.
Cavnar, Michael J.
Kim, Teresa S.
Sadot, Eran
Zeng, Shan
Greer, Jonathan B.
Seifert, Adrian M.
Cohen, Noah A.
Crawley, Megan H.
Green, Benjamin L.
Klimstra, David S.
DeMatteo, Ronald P.
author_facet Sorenson, Eric C.
Khanin, Raya
Bamboat, Zubin M.
Cavnar, Michael J.
Kim, Teresa S.
Sadot, Eran
Zeng, Shan
Greer, Jonathan B.
Seifert, Adrian M.
Cohen, Noah A.
Crawley, Megan H.
Green, Benjamin L.
Klimstra, David S.
DeMatteo, Ronald P.
author_sort Sorenson, Eric C.
collection PubMed
description Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of HCC that most frequently affects young adults. Because of its rarity and an absence of preclinical models, our understanding of FL-HCC is limited. Our objective was to analyze chromosomal alterations and dysregulated gene expression in tumor specimens collected at a single center during two decades of experience with FL-HCC. We analyzed 38 specimens from 26 patients by array comparative genomic hybridiziation (aCGH) and 35 specimens from 15 patients by transcriptome sequencing (RNA-seq). All tumor specimens exhibited genomic instability, with a higher frequency of genomic amplifications or deletions in metastatic tumors. The regions encoding 71 microRNAs (miRs) were deleted in at least 25% of tumor specimens. Five of these recurrently deleted miRs targeted the insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) gene product, and a correlating 100-fold upregulation of IGF2BP1 mRNA was seen in tumor specimens. Transcriptome analysis demonstrated intrapatient tumor similarity, independent of recurrence site or time. The p53 tumor suppressor pathway was downregulated as demonstrated by both aCGH and RNA-seq analysis. Notch, EGFR, NRAS, and RB1 pathways were also significantly dysregulated in tumors compared with normal liver tissue. The findings illuminate the genomic and transcriptomic landscape of this rare disease and provide insight into dysregulated oncogenic pathways and potential therapeutic targets in FL-HCC.
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spelling pubmed-54235882017-05-15 Genome and transcriptome profiling of fibrolamellar hepatocellular carcinoma demonstrates p53 and IGF2BP1 dysregulation Sorenson, Eric C. Khanin, Raya Bamboat, Zubin M. Cavnar, Michael J. Kim, Teresa S. Sadot, Eran Zeng, Shan Greer, Jonathan B. Seifert, Adrian M. Cohen, Noah A. Crawley, Megan H. Green, Benjamin L. Klimstra, David S. DeMatteo, Ronald P. PLoS One Research Article Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of HCC that most frequently affects young adults. Because of its rarity and an absence of preclinical models, our understanding of FL-HCC is limited. Our objective was to analyze chromosomal alterations and dysregulated gene expression in tumor specimens collected at a single center during two decades of experience with FL-HCC. We analyzed 38 specimens from 26 patients by array comparative genomic hybridiziation (aCGH) and 35 specimens from 15 patients by transcriptome sequencing (RNA-seq). All tumor specimens exhibited genomic instability, with a higher frequency of genomic amplifications or deletions in metastatic tumors. The regions encoding 71 microRNAs (miRs) were deleted in at least 25% of tumor specimens. Five of these recurrently deleted miRs targeted the insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) gene product, and a correlating 100-fold upregulation of IGF2BP1 mRNA was seen in tumor specimens. Transcriptome analysis demonstrated intrapatient tumor similarity, independent of recurrence site or time. The p53 tumor suppressor pathway was downregulated as demonstrated by both aCGH and RNA-seq analysis. Notch, EGFR, NRAS, and RB1 pathways were also significantly dysregulated in tumors compared with normal liver tissue. The findings illuminate the genomic and transcriptomic landscape of this rare disease and provide insight into dysregulated oncogenic pathways and potential therapeutic targets in FL-HCC. Public Library of Science 2017-05-09 /pmc/articles/PMC5423588/ /pubmed/28486549 http://dx.doi.org/10.1371/journal.pone.0176562 Text en © 2017 Sorenson et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Sorenson, Eric C.
Khanin, Raya
Bamboat, Zubin M.
Cavnar, Michael J.
Kim, Teresa S.
Sadot, Eran
Zeng, Shan
Greer, Jonathan B.
Seifert, Adrian M.
Cohen, Noah A.
Crawley, Megan H.
Green, Benjamin L.
Klimstra, David S.
DeMatteo, Ronald P.
Genome and transcriptome profiling of fibrolamellar hepatocellular carcinoma demonstrates p53 and IGF2BP1 dysregulation
title Genome and transcriptome profiling of fibrolamellar hepatocellular carcinoma demonstrates p53 and IGF2BP1 dysregulation
title_full Genome and transcriptome profiling of fibrolamellar hepatocellular carcinoma demonstrates p53 and IGF2BP1 dysregulation
title_fullStr Genome and transcriptome profiling of fibrolamellar hepatocellular carcinoma demonstrates p53 and IGF2BP1 dysregulation
title_full_unstemmed Genome and transcriptome profiling of fibrolamellar hepatocellular carcinoma demonstrates p53 and IGF2BP1 dysregulation
title_short Genome and transcriptome profiling of fibrolamellar hepatocellular carcinoma demonstrates p53 and IGF2BP1 dysregulation
title_sort genome and transcriptome profiling of fibrolamellar hepatocellular carcinoma demonstrates p53 and igf2bp1 dysregulation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423588/
https://www.ncbi.nlm.nih.gov/pubmed/28486549
http://dx.doi.org/10.1371/journal.pone.0176562
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