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Pan-cancer analysis distinguishes transcriptional changes of aneuploidy from proliferation

Patterns of gene expression in tumors can arise as a consequence of or result in genomic instability, characterized by the accumulation of somatic copy number alterations (SCNAs) and point mutations (PMs). Expression signatures have been widely used as markers for genomic instability, and both SCNAs...

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Autores principales: Buccitelli, Christopher, Salgueiro, Lorena, Rowald, Konstantina, Sotillo, Rocio, Mardin, Balca R., Korbel, Jan O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378169/
https://www.ncbi.nlm.nih.gov/pubmed/28320919
http://dx.doi.org/10.1101/gr.212225.116
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author Buccitelli, Christopher
Salgueiro, Lorena
Rowald, Konstantina
Sotillo, Rocio
Mardin, Balca R.
Korbel, Jan O.
author_facet Buccitelli, Christopher
Salgueiro, Lorena
Rowald, Konstantina
Sotillo, Rocio
Mardin, Balca R.
Korbel, Jan O.
author_sort Buccitelli, Christopher
collection PubMed
description Patterns of gene expression in tumors can arise as a consequence of or result in genomic instability, characterized by the accumulation of somatic copy number alterations (SCNAs) and point mutations (PMs). Expression signatures have been widely used as markers for genomic instability, and both SCNAs and PMs could be thought to associate with distinct signatures given their different formation mechanisms. Here we test this notion by systematically investigating SCNA, PM, and transcriptome data from 2660 cancer patients representing 11 tumor types. Notably, our data indicate that similar expression signatures can be derived from correlating gene expression with either SCNA or PM load. Gene sets related to cell growth and proliferation generally associated positively, and immunoregulatory gene sets negatively, with variant burden. In-depth analyses revealed several genes whose de-regulation correlates with SCNA but not with PM burden, yielding downstream effectors of TP53 and MYC signaling unique to high-SCNA tumors. We compared our findings to expression changes observed in two different cancer mouse models with persistent mitotic chromosomal instability, observing a decrease in proliferative expression signatures. Our results suggest that overexpression of cell-cycle–related genes are a characteristic of proliferation, and likely tumor evolution, rather than ongoing genomic instability.
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spelling pubmed-53781692017-10-01 Pan-cancer analysis distinguishes transcriptional changes of aneuploidy from proliferation Buccitelli, Christopher Salgueiro, Lorena Rowald, Konstantina Sotillo, Rocio Mardin, Balca R. Korbel, Jan O. Genome Res Research Patterns of gene expression in tumors can arise as a consequence of or result in genomic instability, characterized by the accumulation of somatic copy number alterations (SCNAs) and point mutations (PMs). Expression signatures have been widely used as markers for genomic instability, and both SCNAs and PMs could be thought to associate with distinct signatures given their different formation mechanisms. Here we test this notion by systematically investigating SCNA, PM, and transcriptome data from 2660 cancer patients representing 11 tumor types. Notably, our data indicate that similar expression signatures can be derived from correlating gene expression with either SCNA or PM load. Gene sets related to cell growth and proliferation generally associated positively, and immunoregulatory gene sets negatively, with variant burden. In-depth analyses revealed several genes whose de-regulation correlates with SCNA but not with PM burden, yielding downstream effectors of TP53 and MYC signaling unique to high-SCNA tumors. We compared our findings to expression changes observed in two different cancer mouse models with persistent mitotic chromosomal instability, observing a decrease in proliferative expression signatures. Our results suggest that overexpression of cell-cycle–related genes are a characteristic of proliferation, and likely tumor evolution, rather than ongoing genomic instability. Cold Spring Harbor Laboratory Press 2017-04 /pmc/articles/PMC5378169/ /pubmed/28320919 http://dx.doi.org/10.1101/gr.212225.116 Text en © 2017 Buccitelli et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research
Buccitelli, Christopher
Salgueiro, Lorena
Rowald, Konstantina
Sotillo, Rocio
Mardin, Balca R.
Korbel, Jan O.
Pan-cancer analysis distinguishes transcriptional changes of aneuploidy from proliferation
title Pan-cancer analysis distinguishes transcriptional changes of aneuploidy from proliferation
title_full Pan-cancer analysis distinguishes transcriptional changes of aneuploidy from proliferation
title_fullStr Pan-cancer analysis distinguishes transcriptional changes of aneuploidy from proliferation
title_full_unstemmed Pan-cancer analysis distinguishes transcriptional changes of aneuploidy from proliferation
title_short Pan-cancer analysis distinguishes transcriptional changes of aneuploidy from proliferation
title_sort pan-cancer analysis distinguishes transcriptional changes of aneuploidy from proliferation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378169/
https://www.ncbi.nlm.nih.gov/pubmed/28320919
http://dx.doi.org/10.1101/gr.212225.116
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