Elsevier

Neoplasia

Volume 14, Issue 11, November 2012, Pages 1087-1096, 1-49
Neoplasia

Long-range Transcriptome Sequencing Reveals Cancer Cell Growth Regulatory Chimeric mRNA

https://doi.org/10.1593/neo.121342Get rights and content
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open access

Abstract

mRNA chimeras from chromosomal translocations often play a role as transforming oncogenes. However, cancer transcriptomes also contain mRNA chimeras that may play a role in tumor development, which arise as transcriptional or post-transcriptional events. To identify such chimeras, we developed a deterministic screening strategy for long-range sequence analysis. High-throughput, long-read sequencing was then performed on cDNA libraries from major tumor histotypes and corresponding normal tissues. These analyses led to the identification of 378 chimeras, with an unexpectedly high frequency of expression (≈2 x 10-5 of all mRNA). Functional assays in breast and ovarian cancer cell lines showed that a large fraction of mRNA chimeras regulates cell replication. Strikingly, chimeras were shown to include both positive and negative regulators of cell growth, which functioned as such in a cell-type-specific manner. Replication-controlling chimeras were found to be expressed by most cancers from breast, ovary, colon, uterus, kidney, lung, and stomach, suggesting a widespread role in tumor development.

Abbreviations

FP
fusion point
NGS
next-generation sequencing
SD
standard deviation

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This work was supported by Fondazione Cassa di Risparmio della Provincia di Chieti, Italian Ministry of Health (RicOncol grant RF-EMR-2006-361866), Fondazione Compagnia di San Paolo (grant 2489IT), Ministero dello Sviluppo-Made in Italy (contract No MI01_00424), and the Italian Foundation for Cancer Research (fellowship to M.T.). This article refers to supplementary materials, which are designated by Tables S1 to S11 and Figures S1 to S4 and are available online at www.neoplasia.com. The Fusion-Miner software is freely available at FusionMiner.sourceforge.net. These authors contributed equally to this work.

a

Current address: Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107.