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Genomic basis for RNA alterations revealed by whole-genome analyses of 27 cancer types

Item Type:Preprint
Title:Genomic basis for RNA alterations revealed by whole-genome analyses of 27 cancer types
Creators Name:Calabrese, C. and Davidson, N.R. and Fonseca, N.A. and He, Y. and Kahles, A. and Lehmann, K.V. and Liu, F. and Shiraishi, Y. and Soulette, C.M. and Urban, L. and Demircioğlu, D. and Greger, L. and Li, S. and Liu, D. and Perry, M.D. and Xiang, L. and Zhang, F. and Zhang, J. and Bailey, P. and Erkek, S. and Hoadley, K.A. and Hou, Y. and Kilpinen, H. and Korbel, J.O. and Marin, M.G. and Markowski, J. and Nandi, T. and Pan-Hammarström, Q. and Pedamallu, C.S. and Siebert, R. and Stark, S.G. and Su, H. and Tan, P. and Waszak, S.M. and Yung, C. and Zhu, S. and Awadalla, P. and Creighton, C.J. and Meyerson, M. and Ouellette, B.F.F. and Wu, K. and Yang, H. and Brazma, A. and Brooks, A.N. and Göke, J. and Rätsch, G. and Schwarz, R.F. and Stegle, O. and Zhang, Z.
Abstract:We present the most comprehensive catalogue of cancer-associated gene alterations through characterization of tumor transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes project. Using matched whole-genome sequencing data, we attributed RNA alterations to germline and somatic DNA alterations, revealing likely genetic mechanisms. We identified 444 associations of gene expression with somatic non-coding single-nucleotide variants. We found 1,872 splicing alterations associated with somatic mutation in intronic regions, including novel exonization events associated with Alu elements. Somatic copy number alterations were the major driver of total gene and allele-specific expression (ASE) variation. Additionally, 82% of gene fusions had structural variant support, including 75 of a novel class called "bridged" fusions, in which a third genomic location bridged two different genes. Globally, we observe transcriptomic alteration signatures that differ between cancer types and have associations with DNA mutational signatures. Given this unique dataset of RNA alterations, we also identified 1,012 genes significantly altered through both DNA and RNA mechanisms. Our study represents an extensive catalog of RNA alterations and reveals new insights into the heterogeneous molecular mechanisms of cancer gene alterations.
Publisher:Cold Spring Harbor Laboratory (U.S.A.)
Article Number:183889
Date:12 March 2018
Official Publication:http://doi.org/10.1101/183889

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