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Processed pseudogenes acquired somatically during cancer development.

ABSTRACT: Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5' truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context.

SUBMITTER: Cooke SL

PROVIDER: S-EPMC3996531 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Processed pseudogenes acquired somatically during cancer development.

Cooke Susanna L SL Shlien Adam A Marshall John J Pipinikas Christodoulos P CP Martincorena Inigo I Tubio Jose M C JM Li Yilong Y Menzies Andrew A Mudie Laura L Ramakrishna Manasa M Yates Lucy L Davies Helen H Bolli Niccolo N Bignell Graham R GR Tarpey Patrick S PS Behjati Sam S Nik-Zainal Serena S Papaemmanuil Elli E Teixeira Vitor H VH Raine Keiran K O'Meara Sarah S Dodoran Maryam S MS Teague Jon W JW Butler Adam P AP Iacobuzio-Donahue Christine C Santarius Thomas T Grundy Richard G RG Malkin David D Greaves Mel M Munshi Nikhil N Flanagan Adrienne M AM Bowtell David D Martin Sancha S Larsimont Denis D Reis-Filho Jorge S JS Boussioutas Alex A Taylor Jack A JA Hayes Neil D ND Janes Sam M SM Futreal P Andrew PA Stratton Michael R MR McDermott Ultan U Campbell Peter J PJ

Nature communications 20140409

Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotransposi ...[more]

PMID: 24714652

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Project description:Processed pseudogenes result from reverse transcribed mRNAs. In general, because processed pseudogenes lack promoters, they are no longer functional from the moment they are inserted into the genome. Subsequently, they freely accumulate substitutions, insertions and deletions. Moreover, the ancestral structure of processed pseudogenes could be easily inferred using the sequence of their functional homologous genes. Owing to these characteristics, processed pseudogenes represent good neutral markers for studying genome evolution. Recently, there is an increasing interest for these markers, particularly to help gene prediction in the field of genome annotation, functional genomics and genome evolution analysis (patterns of substitution). For these reasons, we have developed a method to annotate processed pseudogenes in complete genomes. To make them useful to different fields of research, we stored them in a nucleic acid database after having annotated them. In this work, we screened both mouse and human complete genomes from ENSEMBL to find processed pseudogenes generated from functional genes with introns. We used a conservative method to detect processed pseudogenes in order to minimize the rate of false positive sequences. Within processed pseudogenes, some are still having a conserved open reading frame and some have overlapping gene locations. We designated as retroelements all reverse transcribed sequences and more strictly, we designated as processed pseudogenes, all retroelements not falling in the two former categories (having a conserved open reading or overlapping gene locations). We annotated 5823 retroelements (5206 processed pseudogenes) in the human genome and 3934 (3428 processed pseudogenes) in the mouse genome. Compared to previous estimations, the total number of processed pseudogenes was underestimated but the aim of this procedure was to generate a high-quality dataset. To facilitate the use of processed pseudogenes in studying genome structure and evolution, DNA sequences from processed pseudogenes, and their functional reverse transcribed homologs, are now stored in a nucleic acid database, HOPPSIGEN. HOPPSIGEN can be browsed on the PBIL (Pole Bioinformatique Lyonnais) World Wide Web server (http://pbil.univ-lyon1.fr/) or fully downloaded for local installation.

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Processed pseudogenes acquired somatically during cancer development.

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Processed pseudogenes acquired somatically during cancer development.

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