Processed pseudogenes acquired somatically during cancer development
Cooke SL., Shlien A., Marshall J., Pipinikas CP., Martincorena I., Tubio JMC., Li Y., Menzies A., Mudie L., Ramakrishna M., Yates L., Davies H., Bolli N., Bignell GR., Tarpey PS., Behjati S., Nik-Zainal S., Papaemmanuil E., Teixeira VH., Raine K., Oameara S., Dodoran MS., Teague JW., Butler AP., Iacobuzio-Donahue C., Santarius T., Grundy RG., Malkin D., Greaves M., Munshi N., Flanagan AM., Bowtell D., Martin S., Larsimont D., Reis-Filho JS., Boussioutas A., Taylor JA., Hayes ND., Janes SM., Futreal PA., Stratton MR., McDermott U., Campbell PJ., Provenzano E., van de Vijver M., Richardson AL., Purdie C., Pinder S., Grogan GM., Vincent-Salomon A., Grabau D., Sauer T., Garred Ø., Ehinger A., Van den Eynden GG., van Deurzen CHM., Salgado R., Brock JE., Lakhani SR., Giri DD., Arnould L., Jacquemier J., Treilleux I., Caldas C., Chin SF., Fatima A., Thompson AM., Stenhouse A., Foekens J., Martens J., Sieuwerts A., Brinkman A., Stunnenberg H., Span PN., Sweep F., Desmedt C., Sotiriou C., Thomas G., Broeks A., Langerod A., Aparicio S., Simpson PT., van ’t Veer L., Eyfjord JE., Hilmarsdottir H., Jonasson JG., Børresen-Dale AL., Ta Michael Lee M., Wong BH., Tee Tan BK., Hooijer GKJ.
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%), 5a €2 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. © 2014 Macmillan Publishers Limited. All rights reserved.