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.

Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution

“…Together with our results, cell adhesion and neuronal genes have repeatedly been reported to be excessively mutagenized by somatic L1 insertions in cancer (Iskow et al 2010;Lee et al 2012;Solyom et al 2012;Ewing et al 2013;Shukla et al 2013;Cooke et al 2014;Helman et al 2014;Tubio et al 2014), and some genes seem to act as hotspots for insertions. Intriguingly, CNTNAP2 (contactin associated protein-like 2, a member of the neurexin family with cell adhesion functions in the nervous system) has been recurrently mutagenized by L1 insertions in four lung and an endometrial carcinoma (Helman et al 2014;Tubio et al 2014).…”

“…4A) that were detectable by conventional PCR, such insertions may exist whose detection could depend on the amount of input DNA used for genotyping and the fraction of cells containing the insertion. This possibility raises questions regarding our TGCT insertion and insertions in previous studies using blood as the normal tissue Ewing et al 2013;Cooke et al 2014;Helman et al 2014;Tubio et al 2014). That is to say, these insertions were not verified in the same normal tissue from which the tumor originated, or in other words, the nature of tumor-specificity versus simply normal tissue-specificity of the insertions is not known.…”

“…This process can lead to insertional mutagenesis and genetic instability (Goodier and Kazazian 2008). Potentially etiological L1 insertions have been reported in APC (Miki et al 1992) and PTEN exons (Helman et al 2014) in colorectal and endometrial cancer, respectively, and insertions of unknown significance have been found in numerous other cancer driver genes in a variety of malignancies (Iskow et al 2010;Lee et al 2012;Solyom et al 2012;Ewing et al 2013;Shukla et al 2013;Cooke et al 2014;Helman et al 2014;Pitkanen et al 2014;Tubio et al 2014;Paterson et al 2015). In a study of somatic retrotransposition during the evolution of prostate and lung cancer, Tubio et al (2014) found evidence of insertions occurring during cancer development.…”

“…In particular, Long INterspersed Element (LINE)-1 (L1)-mediated retrotransposition has been observed mostly in epithelial cancers. Somatic human-specific L1 (L1Hs) insertions are most abundant in these cancers, but L1-mediated Alu, SVA, and processed pseudogene insertions have also been detected (Iskow et al 2010;Lee et al 2012;Solyom et al 2012;Ewing et al 2013;Shukla et al 2013;Cooke et al 2014;Helman et al 2014;Pitkanen et al 2014;Tubio et al 2014). L1s are autonomous mobile elements that comprise 17% of the human genome and retrotranspose by a "copy and paste" mechanism via an RNA intermediate.…”

LINE-1 in cancer: multifaceted functions and potential clinical implications

“…13 During TPRT, ORF2p endonuclease generates nicks in genomic DNA to expose 3′-OH ends, which serve as primers to synthesize L1 cDNAs by ORF2p RT (Figure 1b). 11 Despite the cis preference of ORF1p and ORF2p for L1 mRNA, the L1 retrotransposition machinery can also reverse-transcribe other RNAs such as Alu RNAs [14][15][16] and SVA RNAs, 15,16 as well as some protein-coding mRNAs, 17 thus inducing mutagenesis and contributing to human genome evolution and diversity.…”