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Recurrent tumor-specific regulation of alternative polyadenylation of cancer-related genes Xue, Zhuyi; Warren, René L; Gibb, Ewan A; MacMillan, Daniel; Wong, Johnathan; Chiu, Readman; Hammond, S. Austin; Yang, Chen; Nip, Ka M; Ennis, Catherine A; et al.

Abstract

Background: Alternative polyadenylation (APA) results in messenger RNA molecules with different 3′ untranslated regions (3’ UTRs), affecting the molecules’ stability, localization, and translation. APA is pervasive and implicated in cancer. Earlier reports on APA focused on 3’ UTR length modifications and commonly characterized APA events as 3’ UTR shortening or lengthening. However, such characterization oversimplifies the processing of 3′ ends of transcripts and fails to adequately describe the various scenarios we observe. Results: We built a cloud-based targeted de novo transcript assembly and analysis pipeline that incorporates our previously developed cleavage site prediction tool, KLEAT. We applied this pipeline to elucidate the APA profiles of 114 genes in 9939 tumor and 729 tissue normal samples from The Cancer Genome Atlas (TCGA). The full set of 10,668 RNA-Seq samples from 33 cancer types has not been utilized by previous APA studies. By comparing the frequencies of predicted cleavage sites between normal and tumor sample groups, we identified 77 events (i.e. gene-cancer type pairs) of tumor-specific APA regulation in 13 cancer types; for 15 genes, such regulation is recurrent across multiple cancers. Our results also support a previous report showing the 3’ UTR shortening of FGF2 in multiple cancers. However, over half of the events we identified display complex changes to 3’ UTR length that resist simple classification like shortening or lengthening. Conclusions: Recurrent tumor-specific regulation of APA is widespread in cancer. However, the regulation pattern that we observed in TCGA RNA-seq data cannot be described as straightforward 3’ UTR shortening or lengthening. Continued investigation into this complex, nuanced regulatory landscape will provide further insight into its role in tumor formation and development.

Item Metadata

Title
Recurrent tumor-specific regulation of alternative polyadenylation of cancer-related genes
Creator
Xue, Zhuyi; Warren, René L; Gibb, Ewan A; MacMillan, Daniel; Wong, Johnathan; Chiu, Readman; Hammond, S. Austin; Yang, Chen; Nip, Ka M; Ennis, Catherine A; Hahn, Abigail; Reynolds, Sheila; Birol, Inanc
Publisher
BioMed Central
Date Issued
2018-07-13
Description
Background: Alternative polyadenylation (APA) results in messenger RNA molecules with different 3′ untranslated regions (3’ UTRs), affecting the molecules’ stability, localization, and translation. APA is pervasive and implicated in cancer. Earlier reports on APA focused on 3’ UTR length modifications and commonly characterized APA events as 3’ UTR shortening or lengthening. However, such characterization oversimplifies the processing of 3′ ends of transcripts and fails to adequately describe the various scenarios we observe. Results: We built a cloud-based targeted de novo transcript assembly and analysis pipeline that incorporates our previously developed cleavage site prediction tool, KLEAT. We applied this pipeline to elucidate the APA profiles of 114 genes in 9939 tumor and 729 tissue normal samples from The Cancer Genome Atlas (TCGA). The full set of 10,668 RNA-Seq samples from 33 cancer types has not been utilized by previous APA studies. By comparing the frequencies of predicted cleavage sites between normal and tumor sample groups, we identified 77 events (i.e. gene-cancer type pairs) of tumor-specific APA regulation in 13 cancer types; for 15 genes, such regulation is recurrent across multiple cancers. Our results also support a previous report showing the 3’ UTR shortening of FGF2 in multiple cancers. However, over half of the events we identified display complex changes to 3’ UTR length that resist simple classification like shortening or lengthening. Conclusions: Recurrent tumor-specific regulation of APA is widespread in cancer. However, the regulation pattern that we observed in TCGA RNA-seq data cannot be described as straightforward 3’ UTR shortening or lengthening. Continued investigation into this complex, nuanced regulatory landscape will provide further insight into its role in tumor formation and development.
Subject
Alternative polyadenylation; Cancer; 3’ UTR; Cleavage site; RNA-Seq; de novo assembly; Trans-ABySS; The Cancer Genome Atlas ; Cloud computing
Genre
Article
Type
Text
Language
eng
Date Available
2018-07-16
Provider
Vancouver : University of British Columbia Library
Rights
Attribution 4.0 International (CC BY 4.0)
DOI
10.14288/1.0368950
URI
http://hdl.handle.net/2429/66499
Affiliation
Medicine, Faculty of; Non UBC; Medical Genetics, Department of
Citation
BMC Genomics. 2018 Jul 13;19(1):536
Publisher DOI
10.1186/s12864-018-4903-7
Peer Review Status
Reviewed
Scholarly Level
Faculty
Copyright Holder
The Author(s).
Rights URI
http://creativecommons.org/licenses/by/4.0/
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Attribution 4.0 International (CC BY 4.0)