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Endogenous retroviral promoter exaptation in human cancer Babaian, Artem; Mager, Dixie L Dec 1, 2016

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REVIEW Open AccessEndogenous retroviral promoter exaptationin human cancerArtem Babaian1,2 and Dixie L. Mager1,2*AbstractCancer arises from a series of genetic and epigenetic changes, which result in abnormal expression or mutationalactivation of oncogenes, as well as suppression/inactivation of tumor suppressor genes. Aberrant expression ofcoding genes or long non-coding RNAs (lncRNAs) with oncogenic properties can be caused by translocations, geneamplifications, point mutations or other less characterized mechanisms. One such mechanism is the inappropriateusage of normally dormant, tissue-restricted or cryptic enhancers or promoters that serve to drive oncogenic geneexpression. Dispersed across the human genome, endogenous retroviruses (ERVs) provide an enormous reservoir ofautonomous gene regulatory modules, some of which have been co-opted by the host during evolution to playimportant roles in normal regulation of genes and gene networks. This review focuses on the “dark side” of suchERV regulatory capacity. Specifically, we discuss a growing number of examples of normally dormant or epigeneticallyrepressed ERVs that have been harnessed to drive oncogenes in human cancer, a process we term onco-exaptation,and we propose potential mechanisms that may underlie this phenomenon.Keywords: Gene regulation, Endogenous retrovirus, Long terminal repeat, Retrotransposon, Epigenetics, Cancer,Alternative promoter, Exaptation, TranscriptionBackgroundSequences derived from transposable elements (TEs) oc-cupy at least half the human genome [1, 2]. TEs are gen-erally classified into two categories; DNA transposons,which comprise 3.2% of the human genome; and the ret-roelements, short interspersed repeats (SINEs, 12.8% ofthe genome), long interspersed repeats (LINEs, 20.7%)and long terminal repeat (LTR) elements, derived fromendogenous retroviruses (ERVs, 8.6%). Over evolutionarytime, TE sequences in the genome can become func-tional units that confer a fitness advantage, a processcalled “exaptation” [3, 4]. Exaptation includes proteincoding, non-coding and regulatory effects of TEs. This isin contrast to the designation of “nonaptations” for gen-etic units that perform some function (such as initiatetranscription) but don’t impact host fitness [4]. Besidestheir roles in shaping genomes during evolution, TEscontinue to have impact in humans through insertionalmutagenesis, inducing rearrangements and affecting generegulation, as discussed in recent reviews [5–12].Efforts to explore the role of TEs in human cancerhave focused primarily on LINEs and ERVs. While nearlyall L1s, the major human LINE family, are defective, afew hundred retain the ability to retrotranspose [13] andthese active elements occasionally cause germ line muta-tions [9, 14, 15]. Several recent studies have also docu-mented somatic, cancer-specific L1 insertions [16–23],and a few such insertions were shown to contribute tomalignancy [9]. For example, two L1 insertions weredocumented to disrupt the tumor suppressor gene APCin colon cancer [16, 23]. However, it is probable thatmost insertions are non-consequential “passenger muta-tions”, as recently discussed by Hancks and Kazazian [9].Thus, the overall biological effect size of LINE retrotran-sposition on the process of oncogenesis may be limited.No evidence for retrotranspositionally active ERVs inhumans has been reported [24–26], so it is unlikely thathuman ERVs activate oncogenes or inactivate tumorsuppressor genes by somatic retrotransposition. This isin contrast to the frequent oncogene activation by inser-tions of exogenous and endogenous retroviruses in* Correspondence: dmager@bccrc.ca1Terry Fox Laboratory, British Columbia Cancer Agency, 675 West 10thAvenue, Vancouver, BC V5Z1L3, Canada2Department of Medical Genetics, University of British Columbia, Vancouver,BC, Canada© The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Babaian and Mager Mobile DNA  (2016) 7:24 DOI 10.1186/s13100-016-0080-xchickens or mice, where retrotranspositional activity ofERVs is very high [27–29]. Therefore, to date, most stud-ies into potential roles for ERVs in human cancer havefocused on their protein products. Indeed, there isstrong evidence that the accessary proteins Np9 andRec, encoded by members of the relatively young HERV-K (HML-2) group, have oncogenic properties, particu-larly in germ cell tumors [30–33].Regardless of their retrotranspositional or coding cap-acity, ERVs may play a broader role in oncogenesis involv-ing their intrinsic regulatory capacity. De-repression/activation of cryptic (or normally dormant) promoters todrive ectopic expression is one mechanism that can leadto oncogenic effects [34–40]. Because TEs, and especiallyERV LTRs, are an abundant reservoir of natural pro-moters in the human genome [6, 41, 42], inappropriatetranscriptional activation of typically repressed LTRs maycontribute to oncogenesis. Here we review examples ofsuch phenomena, which we term “onco-exaptation”, andpropose two explanatory models to understand the role ofLTRs in oncogenesis.Promoter potential of ERVsHundreds of ERV “families” or groups, which is themore proper designation [43], are remnants of ancientretroviral infections of the germ line and occupy at least8.67% of the human genome [1, 24, 44]. These rangefrom groups that integrated before the divergence of ro-dents and primates, such as older members of the largeMaLR/ERV-L class, to the youngest HERV-K (HML-2)group, a few members of which are insertionally poly-morphic in humans [45, 46]. While it has been postu-lated that rare “active” HERV-K elements exist at verylow allele frequencies [45], there is currently no evi-dence for new somatic or germ line insertions of ERVsin humans and nearly all have lost coding potential[24–26]. The situation is starkly different in inbredmice, where at least 10% of documented, phenotype-producing germ line mutations and numerous somatic,cancer-associated insertions are due to ongoing retro-transpositions of ERVs [28, 29, 47]. Table 1 lists selectmajor ERV groups found in humans, members of whichare mentioned in this review.Approximately 90% of the “ERV-related” human gen-omic DNA is in the form of solitary LTRs, which are cre-ated over evolutionary time via recombination betweenthe 5’ and 3’ LTRs of an integrated provirus [48, 49].LTRs naturally contain transcriptional promoters andenhancers, and often splice donor sites, required for au-tonomous expression of the integrated LTR element.Furthermore, unlike for LINEs (see below), the integra-tion process nearly always retains the primary tran-scriptional regulatory motifs, i.e. the LTR, even afterrecombination between the LTRs of a full-length proviralform. Mutations will degrade LTR promoter/enhancermotifs over time, but many of the >470,000 ERV/LTR lociin the genome [50] likely still retain some degree of theirancestral promoter/enhancer function, and hence a generegulatory capacity.LTR-mediated regulation of single genes and gene net-works has been increasingly documented in the litera-ture. For example, studies have implicated ERV LTRs inspecies-specific regulatory networks in ES cells [51], inthe interferon response [52], in p53-mediated regulation[53], as tissue-specific enhancers [54, 55] and in regulat-ing pluripotency by promoting genes and lncRNAs instem cells [56–60]. LTR regulatory capacity arises fromboth their “ready-to-use” ancestral transcriptional factor(TF) binding sites and by mutation/evolution of novelsites, possibly maintained through epistatic capture [61](recently reviewed in [42]). For more in depth discussionof the evolutionary exaptation of enhancers/promotersof LTRs and other TEs in mammals, we refer the readerto a rapidly growing number of reviews on this subjectTable 1 ERV/LTR groups mentioned in this reviewERV Class ERV Group Associated LTRs (Repbase names) ~Copies of internal regionsa ~Copies of solitary LTRsbI (ERV1) HERV-H LTR7, 7B, 7C, 7Y 1060 1270HERV-9 LTR12, 12B-12 F 450 6500HERV-E LTR2, 2B, 2C 250 720HUERS-P2 LTR1, 1A-1 F 120 3000LOR1 LOR1a, 1b 175 1080MER41 MER41A-41G 275 4110II (ERVK) HERV-K (HML-2) LTR5, 5A, 5B, 5Hs 80 1200III (ERVL) HERV16 LTR16A-16E 860 18100III (MaLR) THE THE1A-1D 7900 21260MLT1 MLT1A-1O 3820 146,550aCopy numbers of internal regions estimated from Dfam (dfam.org) [50]bSolitary LTR numbers estimated from Dfam coverage minus 2x internal region numbers, assuming all internal regions are associated with two LTRsBabaian and Mager Mobile DNA  (2016) 7:24 Page 2 of 21[6, 10, 42, 62–65]. Suffice it to say that, retrotransposi-tionally incompetent ERV LTRs, long considered the“poor cousin” of active L1 elements, have emerged fromthe shadowy realm of junk DNA and are now recognizedas a major source of gene regulatory evolution throughexaptation of their promoters and enhancers.Promoter potential of LINEs and other non-LTR TEsBesides via new retrotransposition events, existing L1 el-ements can also impact genes through promoter dona-tion. Full-length L1 elements harbor two internalpromoters at their 5’ end, a sense promoter that drives ex-pression of the element and an antisense promoter thathas been shown to control expression of nearby genesthrough formation of chimeric transcripts [66–69]. Re-cently, this antisense promoter was also shown to promoteexpression of a small protein ORF0, which plays a regula-tory role in retrotransposition [70]. While there are ap-proximately 500,000 L1 loci in the human genome [1], thevast majority of them are 5’ truncated due to incompletereverse transcription during the retrotranspositionprocess. Only ~3500-7000 are full length, retaining theirpromoters and hence, the potential ability to lend thesepromoters to nearby genes [71, 72]. Therefore, irrespectiveof differences in promoter strength, epigenetic regulationor mutational degradation, the vast copy number differ-ence (~500,000 LTRs versus ~5000 promoter-containingL1s), is likely a major reason why the great majority ofTE-initiated transcripts involve LTRs rather than L1s. Ingenome-wide screens of TE-initiated transcripts, smallfragments of old L2 elements, which do not span the ca-nonical L2 promoter, can be found as TSSs of lowlyexpressed transcripts [73] (unpublished data). Such in-stances likely represent “de novo” promoters, those arisingnaturally from genomic DNA which happens to be de-rived from a TE fragment, (possibly because L2 fragmentshave a GC rich base composition), rather than an “ances-tral” or “ready-made” promoter, one which utilizes a TE’soriginal regulatory sequence.Human SINE elements, namely ALUs and the olderMIRs, can also promote transcription of nearby genesbut these instances are relatively rare [68] given their ex-tremely high copy numbers (~1.85 million fragments)[50]. This likely partly reflects the fact that SINEs, beingderived from small functional RNAs, inherently possessPolIII promoters, rather than PolII, and their autono-mous promoter strength is weak [74, 75]. Old MIR ele-ments, as well as other ancient SINEs and DNA TEs,have been more prominent as enhancers, rather thangenic promoters, as shown in several studies [76–81].TEs and the cancer transcriptomeWhile some TE components have assumed cellular func-tions over evolutionary time, such as the syncytin genesin mammalian placenta, derived from independent ERVenv genes in multiple mammals [6, 44, 82–84], the vastmajority of TE/ERV insertions will be neutral or detri-mental to the host. Given the potential for harm, mul-tiple host mechanisms to repress these sequences haveevolved. In mammals, ERV and L1 transcription is sup-pressed in normal cells by DNA methylation and/orhistone modifications as well as many other host fac-tors [9, 85–92]. The epigenetic regulation of TEs isrelevant in cancer because epigenetic changes are com-mon in malignancy and frequently associated with mu-tations in “epigenome-modifying” genes [93–97]. Whilethe ultimate effects of many such mutations are not yetclear, their prominence indicates a central role for epi-genomic dysregulation in oncogenesis [94, 98]. Themost well established epigenetic changes are promoterhypermethylation and associated silencing of tumorsuppressor genes [95, 99, 100] as well as genome-wideDNA hypomethylation [101–103]. Hypomethylation ofERVs and L1s in many tumors has been documented[104–106] and general transcriptional up-regulation ofERVs and L1s is often observed in cancers [33, 107–109].However, other studies have shown no significant changesin ERV expression in selected human cancers comparedto corresponding normal tissues [110, 111].General conclusions about overall TE transcriptionalderegulation in malignancy, or in any other biologicalstate, are not always well founded and can depend onthe type and sensitivity of the assay. For example, ex-pression studies that use consensus probes for internalL1 or ERV regions to assay expression by custom micro-arrays or RT-PCR don’t resolve individual loci, so highexpression signals could reflect dispersed transcriptionalactivation of many elements or the high expression ofonly one or a few loci. Such assays typically also cannotdistinguish between expression due to TE promoter de-repression or due to increased transcription of tran-scripts harboring TEs. RNA-Seq has the potential to giveinformation on expression of individual TE loci, but in-terpretations of expression levels can be confounded bymapping difficulties, length of read and sequencingdepth [112]. In any event, in most cases where transcrip-tional up-regulation of TE groups or individual TEs hasbeen detected in cancer, the biological relevance of suchaberrant expression is poorly understood.Onco-exaptation of ERV/TE promotersWe propose that transcriptional up-regulation of LTR(and to a lesser extent L1) promoters is widespread inepigenetically perturbed cells such as cancer cells. Herewe present specific published examples of onco-exaptation of TE-derived promoters affecting protein-coding genes (Table 2, Fig. 1). Although many otherTE-initiated transcripts have been identified in cancerBabaian and Mager Mobile DNA  (2016) 7:24 Page 3 of 21cells (see below), in this section we restrict the discus-sion to those cases where some role of the TE-drivengene in cancer or cell growth has been demonstrated.Ectopic and overexpression of protein-coding genesThe most straightforward interaction between a TE pro-moter and a gene is when a TE promoter is activated,initiates transcription, and transcribes a downstreamgene without altering the open reading frame (ORF),thus serving as an alternative promoter. Since the TEpromoter may be regulated differently than the nativepromoter, this can result in ectopic and/or overexpres-sion of the gene, with oncogenic consequences.The first case of such a phenomenon was discoveredin the investigation of a potent oncogene colony stimu-lating factor one receptor (CSF1R) in Hodgkin Lymph-oma (HL). Normally, CSF1R expression is restricted tomacrophages in the myeloid lineage. To understand howthis gene is expressed in HL, a B-cell derived cancer,Lamprecht et al. [113] performed 5’ RACE which re-vealed that the native, myeloid-restricted promoter is si-lent in HL cell lines, with CSF1R expression insteadbeing driven by a solitary THE1B LTR, of the MaLR-ERVL class (Fig. 1a). THE1B LTRs are ancient, found inboth Old and New World primates, and are highlyabundant in the human genome, with a copy number of~17,000 [50, 114] (Table 1). The THE1B-CSF1R tran-script produces a full-length protein in HL, which is re-quired for growth/survival of HL cell lines [113] and isclinically prognostic for poorer patient survival [115].Ectopic CSF1R expression in HL appears to be com-pletely dependent on the THE1B LTR, and CSF1R pro-tein or mRNA is detected in 39–48% of HL patientsamples [115, 116].To detect additional cases of onco-exaptation, wescreened whole transcriptomes (RNA-Seq libraries) froma set of HL cell lines as well as from normal human Bcells for TE-initiated transcripts, specifically transcriptsthat were recurrent in HL and not present in normal Bcells [117]. We identified the Interferon RegulatoryFactor 5 gene (IRF5) as a recurrently up-regulated genebeing promoted by a LOR1a LTR located upstream ofthe native/canonical TSS (Fig. 1b). LOR1a LTRs aremuch less abundant compared to THE1 LTRs (Table 1)but are of similar age, with the IRF5 copy havinginserted prior to New World-Old World primate diver-gence. IRF5 has multiple promoters/TSSs and complextranscription [118] and, contrary to the CSF1R case, thenative promoters are not completely silent in HL. How-ever, LTR activity correlates with strong overexpressionof the IRF5 protein and transcript, above normal physio-logical levels [117]. While our study was ongoing, Kreheret al. reported that IRF5 is upregulated in HL and is acentral regulator of the HL transcriptome [119]. More-over, they found that IRF5 is crucial for HL cell survival.Intriguingly, we noted that insertion of the LOR1a LTRcreated an interferon regulatory factor-binding element(IRFE) that overlaps the 5’ end of the LTR. This IRFEwas previously identified to be critical for promoter ac-tivity as a positive feedback loop through binding ofvarious IRFs, including IRF5 itself [120]. Hence, the in-herent promoter motifs of the LTR, coupled with thecreation of the IRFE upon insertion, combined to pro-vide an avenue for ectopic expression of IRF5 in HL.Expression of truncated proteinsIn these cases, a TE-initiated transcript results in the ex-pression of a truncated open reading frame of the af-fected gene, typically because the TE is located in anintron, downstream of the canonical translational startsite. The TE initiates transcription, but the final tran-script structure depends on the position of downstreamsplice sites, and protein expression requires usage of adownstream ATG. Protein truncations can result inoncogenic effects due to loss of regulatory domains orthrough other mechanisms, with a classic example beingTable 2 Activation of oncogenes by Onco-exaptation of TE-derived promotersGenea Gene function Primary result of TE-drivenexpressionTE type TE promoter coordinates(hg38)Cancer type referencesCSF1R Tyrosine kinase receptor Ectopic expression ofnormal protein(ERVL-MaLR) THE1B LTR chr5:150092453–150092809 HL [113]IRF5 Transcription factor Ectopic expression ofnormal protein(ERV1) LOR1a LTR chr7:128936859–128937097 HL [117, 119]MET Tyrosine kinase receptor Protein truncation (L1) L1PA2 chr7:116718498–116724489 CML, others? [124, 125]ALK Tyrosine kinase receptor Protein truncation (ERVL) LTR16B2 chr2:29223783–29224196 melanoma [38]ERRB4 Tyrosine kinase receptor Protein truncation (ERVL-MaLR) MLT1C LTR(ERVL-MaLR) MLT1H2 LTRchr2:211693702–211694209chr2:211465146–211465419ALCL [129]SLCO1B3 Anion transporter Chimeric protein (ERV1) LTR7b chr12:20822187–20822617 colon, others [133, 136]FABP7 Fatty acid binding Chimeric protein (ERV1) LTR2 chr6:122748805–122749262 DLBCL [138]aOnly those cases with supporting evidence of a role in the cancer are listedbThe fact that the promoter for these isoforms is an LTR was not noted in the cited papersBabaian and Mager Mobile DNA  (2016) 7:24 Page 4 of 21Fig. 1 (See legend on next page.)Babaian and Mager Mobile DNA  (2016) 7:24 Page 5 of 21v-myb, a truncated form of myb carried by acutely trans-forming animal retroviruses [121, 122].The first such reported case involving a TE was identi-fied in a screen of human ESTs to detect transcriptsdriven by the antisense promoter within L1 elements.Mätlik et al. identified an L1PA2 within the second in-tron of the proto-oncogene MET (MET proto-oncogene,receptor tyrosine kinase) that initiates a transcript bysplicing into downstream MET exons (Fig. 1c) [67]. Notsurprisingly, transcriptional activity of the CpG rich pro-moter of this L1 in bladder and colon cancer cell lines isinversely correlated to its degree of methylation [123, 124].A slightly truncated MET protein is produced by the TE-initiated transcript and one study reported that L1-driventranscription of MET reduces overall MET protein levelsand signaling, although by what mechanism is not clear[124]. Analyses of normal colon tissues and matched pri-mary colon cancers and liver metastasis samples showedthis L1 is progressively demethylated in the metastasissamples, which strongly correlates with increased L1-METtranscripts and protein levels [125]. Since MET levels are anegative prognostic indicator for colon cancer [126], thesefindings suggest an oncogenic role for L1-MET.More recently, Wiesner et al. identified a novel iso-form of the receptor tyrosine kinase (RTK), anaplasticlymphoma kinase (ALK), initiating from an alternativepromoter in its 19th intron [38]. This alternative tran-scription initiation (ATI) isoform or ALKATI was re-ported to be specific to cancer samples and found in~11% of skin cutaneous melanomas. ALKATI transcriptsproduce three protein isoforms encoded by exons 20 to29. These smaller isoforms exclude the extracellular do-main of the protein but contain the catalytic intracellulartyrosine kinase domain. This same region of ALK iscommonly found fused with a range of other genes viachromosomal translocations in lymphomas and a varietyof solid tumors [127]. In the Wiesner et al. study it wasfound that ALKATI stimulates several oncogenic signal-ing pathways, drives cell proliferation in vitro, and pro-motes tumor formation in mice [38].The ALKATI promoter is a sense-oriented solitary LTR(termed LTR16B2) derived from the ancient ERVL fam-ily (Fig. 1d). LTR16B2 elements are found in severalhundred copies in both primates and rodents [50, 114]and this particular element is present in the orthologousposition in mouse. Therefore, the promoter potential ofthis LTR has been retained for at least 70 million years.Although not the first such case, the authors state thattheir findings “suggest a novel mechanism of oncogeneactivation in cancer through de novo alternative tran-script initiation”. Evidence that this LTR is at least occa-sionally active in normal human cells comes fromCapped Analysis of Gene Expression (CAGE) analysisthrough the FANTOM5 project [128]. A peak of CAGEtags from monocyte-derived macrophages and endothe-lial progenitor cells occurs within this LTR, 60 bp down-stream of the TSS region identified by Wiesner et al.[38] (Fig. 2a), although a biological function, if any, ofthis isoform in normal cells is unknown.To gain a molecular understanding of ALK-negativeanaplastic large-cell lymphoma (ALCL) cases, Scarfo etal. conducted gene expression outlier analysis and identi-fied high ectopic co-expression of ERBB4 and COL29A1in 24% of such cases [129]. Erb-b2 receptor tyrosine kin-ase 4 (ERBB4), also termed HER4, is a member of theERBB family of RTKs, which includes EGFR and HER2,and mutations in this gene have been implicated insome cancers [130]. Analysis of the ERRB4 transcriptsexpressed in these ALCL samples revealed two iso-forms initiated from alternative promoters, one withinintron 12 (I12-ERBB4) and one within intron 20 (I20-ERBB4), with little or no expression from the native/canonical promoter. Both isoforms produce truncatedproteins that show oncogenic potential, either alone(See figure on previous page.)Fig. 1 Examples of Onco-exaptation. Gene models of known TE-derived promoters expressing downstream oncogenes and listed in Table 2.Legend is shown at the top. a 6 kb upstream of CSF1R, a THE1B LTR initiates transcription and contains a splice donor site which joins to an exonwithin a LINE L1MB5 element and then into the first exon of CSF1R. The TE-initiated transcript has a different, longer 5’ UTR than the canonicaltranscript but the same full-length protein coding sequence. b An LOR1a LTR initiates transcription and splices into the canonical second exon ofIRF5 that contains the standard translational initiation site (TIS) to produce a full-length protein. There also is a novel second exon which is non-TE derived which is incorporated into a minor isoform of LOR1a-IRF5. c Within the canonical intron 2 of the proto-oncogene MET, a full lengthLINE L1PA2 element initiates transcription (anti-sense to itself), splicing through a short exon in a SINE MIR element and into the third exon ofMET. The first TIS of the canonical MET transcript is 14 bp into exon 2, although an alternative TIS exists in exon 3, which is believed to also beused by the L1-promoterd isoform. d An LTR16B2 element in intron 19 of the ALK gene initiates transcription and transcribes into the canonicalexon 20 of ALK. An in-frame TIS within the 20th exon results in translation of a shortened oncogenic protein containing only the intra-cellulartyrosine kinase domain, but lacking the transmembrane and extracellular receptor domains of ALK. e There are two TE-promoted isoforms ofERBB4, the minor variant initiates in an MLT1C LTR in the 12th intron and the major variant initiates in a MLT1H LTR in the 20th intron. Bothisoforms produce a truncated protein, although the exact translation start sites are not defined. f In the third exon of SLCO1B3, two adjacent partlyfull-length HERV elements conspire to create a novel first exon. Transcription initiates in the anti-sense orientation from an LTR7 andtranscribes to a sense-oriented splice donor in an adjacent MER4C LTR, which then splices into the fourth exon of SLCO1B3, creating a smallerprotein. g An LTR2 element initiates anti-sense transcription (relative to its own orientation) and splices into the native second exon of FABP7. TheLTR-derived isoform has a non-TE TIS and splice donor which creates a different N-terminal protein sequence of FABP7Babaian and Mager Mobile DNA  (2016) 7:24 Page 6 of 21(I12 isoform) or in combination. Remarkably, bothpromoters are LTR elements of the ancient MaLR-ERVL class (Fig. 1e). Of note, Scarfo et al. reportedthat two thirds of ERBB4 positive cases showed a“Hodgkin-like” morphology, which is normally foundin only 3% of ALCLs [129]. We therefore examinedour previously published RNA-Seq data from 12 HLcell lines [117] and found evidence for transcriptionfrom the intron 20 MLTH2 LTR in two of these lines(unpublished observations), suggesting that truncatedERBB4 may play a role in some HLs.TE-promoted expression of chimeric proteinsPerhaps the most fascinating examples of onco-exaptationinvolve generation of a novel “chimeric” ORF via usage ofa TE promoter that fuses otherwise non-coding DNA todownstream gene exons. These cases involve both proteinand transcriptional innovation and the resulting productcan acquire de novo oncogenic potential.The solute carrier organic anion transporter familymember 1B3, encodes organic anion transporting poly-peptide 1B3 (OATP1B3, or SLCO1B3), is a 12-transmembrane transporter with normal expressionand function restricted to the liver [131]. Severalstudies have shown that this gene is ectopicallyexpressed in solid tumors of non-hepatic origin, par-ticularly colon cancer [131–134]. Investigations intothe cause of this ectopic expression revealed that thenormal liver-restricted promoter is silent in these can-cers, with expression of “cancer-type” (Ct)-OATP1B3being driven from an alternative promoter in the sec-ond canonical intron [133, 134]. While not previouslyreported as being within a TE, we noted that this alter-native promoter maps within the 5’ LTR (LTR7) of apartly full-length antisense HERV-H element that ismissing the 3’ LTR. Expression of HERV-H itself andLTR7-driven chimeric long non-coding RNAs is anoted feature of embryonic stem cells and normal earlyembryogenesis, where several studies indicate an intri-guing role for this ERV group in pluripotency (for re-cent reviews see [8, 10, 60]). A few studies have alsonoted higher general levels of HERV-H transcription incolon cancer [109, 135]. The LTR7-driven isoform ofSLCO1B3 makes a truncated protein lacking the first28 amino acids but also includes protein sequencefrom the LTR7 and an adjacent MER4C LTR (Fig. 1f ).The novel protein is believed to be intracellular and itsrole in cancer remains unclear. However, one studyFig. 2 a UCSC Genome Browser view (hg19) of a portion of the human ALK gene. ALK exon 20 (large blue box) and a part of the upstreamintron are shown, with direction of transcription from right to left. The LTR16B2 alternative promoter shown in the Repeatmasker track as anorange box and the 25 bp region of clustered TSSs in melanoma cells, identified using 5’ RACE by Weiser et al. [38], is shown as a green box TheCAGE track above is from the Fantom5 project [128], with transcriptional direction indicated with a blue arrow. Most CAGE tags are frommonocyte-derived macrophages and endothelial progenitor cells. b UCSC Genome Browser view (hg19) of the region encompassing the SAMMSONlncRNA, which plays an oncogenic role in melanoma [161]. The LTR1A2 promoter is indicated in the Repeatmasker track as an orange box.The ChIP-Seq track for SOX10 was created from a dataset (NCBI Gene Expression Omnibus: GSE61967) generated by Laurette et al. [225] in the501Mel melanoma cell lineBabaian and Mager Mobile DNA  (2016) 7:24 Page 7 of 21showed that high expression of this isoform is corre-lated with reduced progression-free survival in coloncancer [136].In another study designed specifically to look for TE-initiated chimeric transcripts, we screened RNA-seq li-braries from 101 patients with diffuse large B-celllymphoma (DLBCL) of different subtypes [137] andcompared to transcriptomes from normal B-cells. Thisscreen resulted in the detection of 98 such transcriptsthat were found in at least two DLBCL cases and nonormals [138]. One of these involved the gene forfatty acid binding protein 7 (FABP7). FABP7, nor-mally expressed in brain, is a member of the FABPfamily of lipid chaperones involved in fatty acid up-take and trafficking [139]. Overexpression of FABP7has been reported in several solid tumor types and isassociated with poorer prognosis in aggressive breastcancer [139, 140]. In 5% of the DLBCL casesscreened, we found that FABP7 is expressed from anantisense LTR2 (the 5’LTR of a HERV-E element)(Fig. 1g). Since the canonical ATG is in the first exonof FABP7, the LTR driven transcript encodes achimeric protein with a different N-terminus (see ac-cession NM_001319042.1) [138]. Functional analysisin DLBCL cell lines revealed that the LTR-FABP7protein isoform is required for optimal cell growthand also has subcellular localization properties dis-tinct from the native form [138].Overall, among all TE types giving rise to chimerictranscripts detected in DLBCL, LTRs were over repre-sented compared to their genomic abundance and,among LTR groups, we found that LTR2 elements andTHE1 LTRs were over represented [138]. As discussedabove, this predominance of LTRs over other TE typesis expected.TE-initiated non-coding RNAs in cancerSince TEs, particularly ERV LTRs, provide a major classof promoters for long non-coding RNAs [56, 141, 142],it is not surprising that multiple LTR-driven lncRNAshave been shown to be involved in cancer. These casescan be broadly divided into those with direct, measur-able oncogenic properties (Table 3) and those with ex-pression correlated with a cancer. It should be notedthat we have likely missed some examples if the natureof the promoter was not highlighted or mentioned inthe original publications. Unlike the coding genes dis-cussed above which have non-TE or native promoters innormal tissues, the lncRNAs described here typicallyhave LTRs as their only promoter in normal or malig-nant cells.TE-initiated LncRNAs with oncogenic propertiesIn an extensive study, Prensner et al. reported that thelncRNA SchLAP1 (SWI/SNF complex antagonist associ-ated with prostate cancer 1) is overexpressed in ~25% ofprostate cancers, is an independent predictor of poorclinical outcomes and is critical for invasiveness and me-tastasis [143]. Intriguingly, they found that SchLAP1 in-hibits the function of the SWI/SNF complex, which isknown to have a tumor suppressor roles [144]. Whilenot mentioned in the main text, the authors report insupplementary data that the promoter for this lncRNAis an LTR (Fig. 3a). Indeed, this LTR is a sense-orientedsolitary LTR12C (of the ERV9 group).Linc-ROR is a non-coding RNA (long intergenic non-protein coding RNA, regulator of reprogramming) pro-moted by the 5’ LTR (LTR7) of a full length HERV-Helement [56] (Fig. 3b) and has been shown to play a rolein human pluripotency [145]. Evidence suggests it actsas a microRNA sponge of miR-145, which is a repressorof the core pluripotency transcription factors Oct4,Nanog and Sox2 [146]. Several recent studies have re-ported an oncogenic role for Linc-ROR in different can-cers by sponging miR-145 [147–149] or through othermechanisms [150, 151].Using Serial Analysis of Gene Expression (SAGE),Rangel et al. identified five Human Ovarian cancer Spe-cific Transcripts (HOSTs) that were expressed in ovariancancer but not in other normal cells or cancer typesTable 3 LTR-driven LncRNAs with oncogenic rolelncRNAa TE type TE promoter coordinates (hg38) Cancer type referencesSchLAP1 (ERV1) LTR12C chr2:180691205–180692425 prostate [143]ROR (ERV1) LTR7 chr18:57072052–57072502 breast, others [147, 150]HOST2 (ERV1) LTR2B chr10:84171987–84172465 ovarian [154]AFAP1-AS1 (ERVL-MaLR) THE1A LTRb chr4:7753884–7754236 several [156, 158]SAMMSON (ERV1) LTR1A2b chr3:69999501–70000359 melanoma [161]HULC (ERVL-MaLR) MLT1A LTR chr6:8652095–8652454 liver [163]UCA1 (ERV1) LTR7C chr19:15828738–15829200 several [165, 167]BANCR (ERV1) MER41B LTR chr9:69306939–69307567 melanoma, others [169]aOnly those cases with supporting evidence of a role in the cancer are listedbThe fact that the promoter is an LTR was not previously notedBabaian and Mager Mobile DNA  (2016) 7:24 Page 8 of 21examined [152]. One of these, HOST2, is annotated as aspliced lncRNA entirely contained within a full lengthHERV-E and promoted by an LTR2B element (Fig. 3c).Perusal of RNA-Seq from the 9 core ENCODE cell linesshows robust expression of HOST2 in GM12878, a B-lymphoblastoid cell line, which extends beyond theHERV-E. As with Linc-ROR, HOST2 appears to play anoncogenic role by functioning as a miRNA sponge ofmiRNA let-7b, an established tumor suppressor [153], inepithelial ovarian cancer [154].The Ref-Seq annotated lncRNA AFAP1 antisense RNA1 (AFAP1-AS1) runs antisense to the actin filament asso-ciated protein 1 (AFAP1) gene and several publicationsreport its up-regulation and association with poor sur-vival in a number of solid tumor types [155–158]. Whilethe oncogenic mechanism of AFAP1-AS1 has not beenextensively studied, one report presented evidence that itpromotes cell proliferation by upregulating RhoA/Rac2signaling [159] and its expression inversely correlateswith AFAP1. Although clearly annotated as initiatingwithin a solitary THE1A LTR (Fig. 3d), this fact has notbeen mentioned in previous publications. In screens forTE-initiated transcripts using RNA-seq data from HLcell lines, we noted recurrent and cancer-specific up-regulation of AFAP1-AS1 (unpublished observations),suggesting that it is not restricted to solid tumors. Theinverse correlation of expression between AFAP1 andAFAP1-AS1 suggests an interesting potential mechanismby which TE-initiated transcription may suppress a gene;where an anti-sense TE-initiated transcript disrupts thetranscription, translation or stability of a tumor suppres-sor gene transcript through RNA interference [160].Fig. 3 Gene models of select lncRNAs initiating within LTRs that are involved in oncogenesis. a A solitary LTR12C element initiates SChLAP1, along inter-genic non-coding RNA. b The 5’ LTR7 of a full-length HERVH element initiates the lncRNA ROR, with an exon partially incorporatinginternal ERV sequence. c The HOST2 lncRNA is completely derived from components of a Harlequin (or HERV-E) endogenous retrovirus and itsflanking LTR2B. d Anti-sense to the AFAP1 gene, a THE1A LTR initiates transcription of the lncRNA AFAP1-AS1. The second exon of AFAP1-AS1overlaps exons 14–16 of AFAP1, possibly leading to RNA interference of the geneBabaian and Mager Mobile DNA  (2016) 7:24 Page 9 of 21The SAMMSON lncRNA (survival associated mito-chondrial melanoma specific oncogenic non-codingRNA), which is promoted by a solitary LTR1A2 element,was recently reported as playing an oncogenic role inmelanoma [161]. This lncRNA is located near themelanoma-specific oncogene MITF and is always in-cluded in genomic amplifications involving MITF. Evenin melanomas with no genomic amplification of thislocus, SAMMSON is expressed in most cases, increasesgrowth and invasiveness and is a target for SOX10 [161],a key TF in melanocyte development which is deregu-lated in melanoma [162]. Interestingly, the two SOX10binding sites near the SAMMSON TSS lie just upstreamand downstream of the LTR (Fig. 2b), suggesting thatboth the core promoter motifs provided by the LTR andadjacent enhancer sites combine to regulate SAMMSON.Other examples of LTR-promoted oncogenic lncRNAsinclude HULC for Highly Upregulated in Liver Cancer[163, 164], UCA1 (urothelial cancer associated 1)[165–168] and BANCR (BRAF-regulated lncRNA 1)[169–171]. Although not mentioned in the originalpaper, three of the four exons of BANCR were shownto be derived from a partly full length MER41 ERV,with the promoter within the 5’LTR of this elementannotated MER41B [141]. Intriguingly, MER41 LTRswere recently shown to harbor enhancers responsiveto interferon, indicating a role for this ERV group inshaping the innate immune response in primates [52].It would be interesting to investigate roles for BANCRwith this in mind.TE-initiated lncRNAs as cancer-specific markersThere are many examples of TE-initiated RNAs with po-tential roles in cancer or which are preferentiallyexpressed in malignant cells but for which a direct onco-genic function has not yet been demonstrated. Still, suchtranscripts may underlie a predisposition for transcrip-tion of specific groups of LTRs/TEs in particular malig-nancies and therefore function as a marker for a canceror cancer subtype. Since these events potentially do notconfer a fitness advantage for the cancer cell, they arenot “exaptations” but “nonaptations” [4].One of these is a very long RNA initiated by the anti-sense promoter of an L1PA2 element as reported byTufarelli’s group and termed LCT13 [172, 173]. EST evi-dence indicates splicing from the L1 promoter to theGNTG1 gene, located over 300 kb away. The tumor sup-pressor gene, tissue factor pathway inhibitor 2, (TFPI-2),which is often epigenetically silenced in cancers [174], isantisense to LCT13 and it was shown that LCT13 tran-script levels are correlated with down regulation ofTFPI-2 and associated with repressive chromatin marksat the TFPI-2 promoter [172].Gibb et al. analyzed RNA-Seq from colon cancers andmatched normal colon to find cancer-associatedlncRNAs and identified an RNA promoted by a solitaryMER48 LTR, which they termed EVADR, for Endogen-ous retroviral-associated ADenocarcinoma RNA [175].Screening of data from The Cancer Genome Atlas(TCGA) [176] showed that EVADR is highly expressedin several types of adenocarcinomas, it is not associatedwith global activation of MER48 LTRs across the gen-ome and its expression correlated with poorer survival[175]. In another study, Gosenca et al. used a custommicroarray to measure overall expression of severalHERV groups in urothelial carcinoma compared to nor-mal urothelial tissue and generally found no difference[111]. However, they found one full-length HERV-Eelement, located in the antisense direction in an intronof the PLA2G4A gene that is transcribed in urothelialcarcinoma and appears to modulate PLA2G4A expres-sion, thereby possibly contributing to carcinogenesis, al-though the mechanism is not clear.By mining long nuclear RNA datasets from ENCODEcell lines, normal blood and Ewing sarcomas, one groupidentified over 2000 very long (~50–700 kb) non codingtranscripts termed vlincRNAs [142]. They found thepromoters for these vlincRNAs to be enriched in LTRs,particularly for cell type-specific vlincRNAs, and themost common transcribed LTR types varied in differentcell types. Moreover, among the datasets examined, theyreported that the number of LTR-promoted vlincRNAscorrelated with degree of malignant transformation,prompting the conclusion that LTR-controlled vlincR-NAs are a “hallmark” of cancer [142].In a genome-wide CAGE analysis of 50 hepatocellularcarcinoma (HCC) primary samples and matched non-tumor tissue, Hashimoto et al. found that many LTR-promoted transcripts are upregulated in HCC, most ofthese apparently associated with non-coding RNAs asthe CAGE peaks in the LTRs are far from annotatedprotein coding genes [177]. Similar results were found inmouse HCC. Among the hundreds of human LTRgroups, they found the LTR-associated CAGE peaks tobe significantly enriched in LTR12C (HERV9) LTRs andmapped the common TSS site within these elements,which agrees with older studies on TSS mapping of thisERV group [178]. Moreover, this group reported thatHCCs with highest LTR activity mostly had a viral(Hepatitis B) etiology, were less differentiated and hadhigher risk of recurrence [177]. This study suggestswidespread tissue-inappropriate transcriptional activityof LTRs in HCC.LTR12s as flexible promoters in cancer and normal tissuesMost recent human ERV LTR research has been fo-cused on HERV-H (LTR7/7Y/7B/7C) due to roles forBabaian and Mager Mobile DNA  (2016) 7:24 Page 10 of 21HERV-H/LTR7-driven RNAs in pluripotency [56–58,60, 179, 180] or on the youngest HERV group,HERV-K (LTR5/5Hs), due to its expression in earlyembryogenesis [181–183], coding capacity of somemembers [30, 184] and potential roles for its proteinsin cancer and other diseases [30–33, 185]. LTR12s(including LTR12B,C,D,E and F subtypes), which arethe LTRs associated with the HERV-9 group [186],are generally of similar age to HERV-H [187] but aremuch more numerous than HERV-H or HERV-K,with solitary LTRs numbering over 6000 (Table 1).There are several examples of LTR12s providing pro-moters for coding genes or lncRNAs in various normaltissues [63, 188–191]. LTR12s, particularly LTR12C, arelonger and more CpG rich than most other ERV LTRs,possibly facilitating development of diverse inherenttissue-specificities and flexible combinations of TF bind-ing sites, which may be less probable for other LTR types.For example, the consensus LTR7 (HERV-H) is 450 bpwhereas LTR12C (of similar age) is 1577 bp [114], whichis usually long for retroviral LTRs. As noted above, LTR12elements are among the most enriched LTR types acti-vated as promoters in HCC [177] and appear to be themost active LTR type in K562 cells [142]. It is importantto point out, however, that only a very small fraction ofgenomic LTR12 copies are transcriptionally active in anyof these contexts, so general conclusions about activity of‘a family of LTRs’ should be made with caution.A number of other recent investigations on LTR12-driven chimeric transcription have been published. Onestudy specifically screened for and detected numerousLTR12-initiated transcripts in ENCODE cell lines, someof which extend over long genomic regions and emanatefrom bidirectional promoters within these LTRs [192].The group of Dobbelstein discovered that a male germline-specific form of the tumor suppressor TP63 gene isdriven by an LTR12C [190]. Interestingly, they foundthat this LTR is silenced in testicular cancer but reacti-vated upon treatment with histone deacetylase inhibitors(HDACi), which also induces apoptosis [190]. In follow-up studies, this group used 3’ RACE to detect moregenes controlled by LTR12s in primary human testis andin the GH testicular cancer cell line and reported hun-dreds of transcripts, including an isoform of TNFRSF10Bwhich encodes the death receptor DR5 [193]. As withTP63, treating GH or other cancer cell lines with HDACinhibitors such as trichostatin A activated expression ofthe LTR12-driven TNFRSF10B and some other LTR12-chimeric transcripts and induced apoptosis [193, 194].Therefore, in some cases, LTR-driven genes can have aproapoptotic role. In accord with this notion is a studyreporting that LTR12 antisense U3 RNAs wereexpressed at higher levels in non-malignant versus ma-lignant cells [195]. It was proposed that the antisenseU3 RNA may act as a trap for the transcription factorNF-Y, known to bind LTR12s [196], and hence partici-pate in cell cycle arrest [195].Chromosomal translocations involving TEs in cancerActivation or creation of oncogenes via chromosomaltranslocations most commonly involves either the fusionof two coding genes or juxtaposition of new regulatorysequences next to a gene, resulting in oncogenic effectsdue to ectopic expression [197]. One might expect someof the latter cases to involve TE-derived promoters/en-hancers but, to date, there are very few well-documentedexamples of this mechanism in oncogenesis. The ETSfamily member ETV1 (ETS variant 1) is a transcriptionfactor frequently involved in oncogenic translocations,particularly in prostate cancer [198]. Although not acommon translocation, Tomlins et al. identified a pros-tate tumor with the 5’ end of a HERV-K (HML-2) elem-ent on chromosome 22q11.23 fused to ETV1 [199]. Thisparticular HERV-K element is a complex locus with two5’ LTRs and is quite highly expressed in prostate cancer[200]. Indeed, while a possible function is unknown, thisHERV-K locus produces a lncRNA annotated as PCAT-14, for prostate cancer–associated ncRNA transcript-14[201]. In the HERV-K-ETV1 fusion case, the resultanttranscript (Genbank Accession EF632111) initiates inthe upstream 5’LTR, providing evidence that the LTRcontrols expression of ETV1.The fibroblast growth factor receptor 1 (FGFR1) geneon chromosome 8 is involved in translocations with atleast 14 partner genes in stem cell myeloproliferativedisorder and other myeloid and lymphoid cancers [202].One of these involves a HERVK3 element on chromo-some 19 and this event creates a chimeric ORF withHERVK3 gag sequences [203]. While it was reportedthat the LTR promoter may contribute to expression ofthe fusion gene [203], no supporting evidence was pre-sented. Indeed, perusal of public expression data(Expressed sequence tags) from a variety of tissues indi-cates that the HERVK3 element on chromosome 19 ishighly expressed, but from a non-ERV promoter just up-stream (see chr19:58,305,253–58,315,303 in human hg38assembly). Therefore, there is little current evidence forLTR/TE promoters playing a role in oncogene activationvia chromosomal translocations or rearrangements.Models for onco-exaptationThe aforementioned cases of onco-exaptation are a dis-tinct mechanism by which proto-oncogenes becomeoncogenic. Classical activating mutations within TEsmay also lead to transcription of downstream oncogenesbut we are unaware of any evidence for DNA mutationsresulting in LTR/TE transcriptional activation, includingcases where local DNA was sequenced [38] (unpublishedBabaian and Mager Mobile DNA  (2016) 7:24 Page 11 of 21results). Thus, it is important to consider the etiologythrough which LTRs/TEs become incorporated into newregulatory units in cancer. The mechanism could pos-sibly be therapeutically or diagnostically important andperhaps even model how TEs influence genome regula-tion in evolutionary time.In some of the above examples, there is no or very lit-tle detectable transcription from the LTR/TE in any celltype other than the cancer type in which it was reported,suggesting the activity is specific to a particular TE in aparticular cancer. In other cases, CAGE or EST datashow that the LTR/TE can be expressed in other normalor cancer cell types, perhaps to a lower degree. Hencethe term “cancer-specific” should be considered a rela-tive one. Indeed, the idea that the same TE-promotedgene transcripts occur recurrently in tumors from inde-pendent individuals is central to understanding howthese transcripts arise. Below we present two modelsthat may explain the phenomenon of onco-exaptation.The De-repression modelLamprecht and co-workers proposed a ‘De-repressionmodel’ for the LTR driven transcription of CSF1R [204].The distinguishing feature of this model is that onco-exaptations arise deterministically, as a consequence ofmolecular changes that occur during oncogenesis,changes which act to de-repress LTRs or other TEs(Fig. 4). It follows that ‘activation’ of normally dormantTEs/LTRs could lead to robust oncogene expression. Inthe CSF1R case, the THE1B LTR, which promotesCSF1R in HL, contains binding sites for the transcriptionfactors Sp1, AP-1 and NF-kB, each of which contributesto promoter activity in a luciferase reporter experiment[113]. High NF-kB activity, which is known to be up-regulated in HL, loss of the epigenetic corepressorCBFA2T3 as well as LTR hypomethylation all correlatedwith CSF1R-positive HL driven by the LTR [113]. Underthe de-repression model, the THE1B LTR is repressed bydefault in the cell but under a particular set ofFig. 4 De-repression model for onco-exaptation. In the normal or pre-malignant state TEs (grey triangles) are largely silenced across the genome.There is low transcriptional activity to produce long non-coding RNA (orange box), or express coding genes in the case of evolutionary exaptations(not shown). The example proto-oncogene (green box) is under the regulatory control of its native, restrictive promoter. During the process oftransformation and/or oncogenesis, a change in the molecular state of the cell occurs leading to loss of TE repressors (black circles), i.e. DNAhypomethylation, loss of transcriptional or epigenetic repressive factors. The change could also be accompanied by a change/gain in activating factoractivities (red and purple shapes). Together these de-repression events result in higher TE promoter activity (orange triangles) and more TE-derivedtranscripts based on the factors that become deregulated. Oncogenic activation of proto-oncogenes is a consequence of a particular molecular milieuthat arises in the cancerous cellsBabaian and Mager Mobile DNA  (2016) 7:24 Page 12 of 21conditions (gain of NF-kB, loss of CBFA2T3, loss ofDNA methylation) the LTR promoter is remodeled intoan active state [204]. More generally, the model proposesthat a particular LTR activation is a consequence of thepathogenic or disrupted molecular state of the cancercell. In a similar vein, Weber et al. proposed that the L1-driven transcription of MET arose as a consequence ofglobal DNA hypomethylation and loss of repression ofTEs in cancer [124].The LOR1a-IRF5 onco-exaptation in HL [117] can beinterpreted using a de-repression model. An interferonregulatory factor binding element site was created at theintersection of the LOR1a LTR and genomic DNA. Innormal and HL cells negative for LOR1a-IRF5, the LTRis methylated and protected from DNAse digestion, astate that is lost in de-repressed HL cells. This transcrip-tion factor-binding motif is responsive to IRF5 itself andcreates a positive feedback loop between the IRF5 andthe chimeric LOR1a-IRF5 transcript. Thus epigeneticde-repression of this element may reveal an oncogenicexploitation, resulting in high recurrence of LOR1a LTR-driven IRF5 in HL [117].A de-repression model explains several experimentalobservations, such as the necessity for a given set of fac-tors to be present (or absent) for a certain promoter tobe active, especially when those factors differ betweencell states. Indeed, experiments probing the mechanismof TE/LTR activation have used this line of reasoning,often focusing on DNA methylation [113, 117, 125, 129].The limitation of these studies is that they fail to deter-mine if a given condition is sufficient for onco-exaptation to arise. For instance, the human genomecontains >37,000 THE1 LTR loci (Table 1), and indeedthis set of LTRs is generally more active in HL cellscompared to B-cells as would be predicted [113] (un-published results). The critical question is why particu-lar THE1 LTR loci, such as THE1B-CSF1R, arerecurrently de-repressed in HL, yet thousands of hom-ologous LTRs are not.The Epigenetic Evolution modelA central premise in the TE field states that TEs can bebeneficial to a host genome since they increase genetic vari-ation in a population and thus increase the rate at whichevolution (by natural selection) occurs [62, 205, 206]. Theepigenetic evolution model for onco-exaptation (Fig. 5)draws a parallel to this premise within the context oftumor evolution.Key to the epigenetic evolution model is that there ishigh epigenetic variance, both between LTR loci and atthe same LTR locus between cells in a population. Thisepigenetic variance fosters regulatory innovation, and in-creases during oncogenesis. In accord with this idea areseveral studies showing that DNA methylation variation,or heterogeneity, increases in tumor cell populations andthis isn’t simply a global hypomethylation relative tonormal cells [207–209] (reviewed in [210]). In contrastto the de-repression model, a particular pathogenic mo-lecular state is not sufficient or necessary for TE-driventranscripts to arise; instead the given state only dictateswhich sets of TEs in the genome are permissive for tran-scription. Likewise, global de-repression events, such asDNA hypomethylation or mutation of epigenetic regula-tors, are not necessary, but would increase the rate atwhich novel transcriptional regulation evolves.Underpinning this model is the idea that LTRs arehighly abundant and self-contained promoters dispersedacross the genome that can stochastically initiate low ornoisy transcription. This transcriptional noise is a kindof epigenetic variation and thus contributes to cell-cellvariation in a population. Indeed, by re-analyzing CAGEdatasets of retrotransposon-derived TSSs published byFaulkner et al. [73], we observed that TE-derived TSSshave lower expression levels and are less reproducible be-tween biological replicates, compared to non-TE pro-moters (unpublished observations). During malignanttransformation, TFs can become deregulated and genome-wide epigenetic perturbations occur [94, 98, 211] whichwould change the set of LTRs that are potentially active aswell as possibly increasing the total level of LTR-driventranscriptional noise. Up-regulation of specific LTR-driventranscripts would initially be weak and stochastic, fromthe set of permissive LTRs. Those cells gaining an LTR-driven transcript which confers a growth advantage wouldthen be selected for, and the resultant oncogene expres-sion would increase in the tumor population as that epial-lele increases in frequency, in a similar fashion asproposed for the epigenetic silencing of tumor suppressorgenes [95, 99, 100]. Notably, this scenario also means thatwithin a tumor, LTR-driven transcription would be subjectto epigenetic bottleneck effects as well, and that transcrip-tional LTR noise can become “passenger” expression sig-nals as the cancer cells undergo somatic, clonal evolution.It may be counter-intuitive to think of evolution andselection as occurring outside the context of geneticvariation, but the fact that both genetic mutations andnon-genetic/epigenetic variants can contribute to somaticevolution of a cancer is becoming clear [209, 212–215].Epigenetic information or variation by definition is trans-mitted from mother to daughter cells. Thus, in the specificcontext of a somatic/asexual cell population such as atumor, this information, which is both variable betweencells in the population and heritable, will be subject toevolutionary changes in frequency. DNA methylation inparticular has a well-established mechanism by which in-formation (mainly gene repression) is transmitted epige-netically from mother to daughter cells [216] and DNAhypomethylation at LTRs often correlates with theirBabaian and Mager Mobile DNA  (2016) 7:24 Page 13 of 21Fig. 5 Epigenetic evolution model for onco-exaptation. In the starting cell population there is a dispersed and low/noisy promoter activity at TEs(colored triangles) from a set of transcriptionally permissive TEs (grey triangles). TE-derived transcript expression is low and variable between cells.Some transcripts are more reliably measurable (orange box). Clonal tumor evolutionary forces change the frequency and expression of TE-derivedtranscripts by homogenizing epialleles and use of TE promoters (highlighted haplotype). A higher frequency of ‘active’ TE epialleles at a locus results inincreased measurable transcripts initiating from that position. TE epialleles that promote oncogenesis, namely onco-exaptations, can be selected forand arise multiple times independently as driver epialleles, in contrast to the more dispersed passenger epialleles, or “nonaptations”Babaian and Mager Mobile DNA  (2016) 7:24 Page 14 of 21expression [113, 117, 217]. Thus, this model suggests thatone important type of “epigenetic variant” or epiallele isthe transcriptional status of the LTR itself, since thephenotypic impact of LTR transcription may be high inonco-exaptation. Especially in light of the fact that largenumbers of these highly homologous sequences arespread across the genome, epigenetic variation, and pos-sibly selection, at LTRs creates a fascinating system bywhich epigenetic evolution in cancer may occur.ConclusionsHere we have reviewed the growing number of exam-ples of LTR/TE onco-exaptation. Although such TEshave the potential to be deleterious by contributing tooncogenesis if transcriptionally activated, their fixationin the genome and ancient origin suggests that theirpresence is not subject to significant negative selection.This could be due to the low frequency of onco-exaptation at a particular TE locus and/or to the factthat cancer is generally a disease that occurs after thereproductive years. However, it is generally assumedthat negative selection is the reason why TEs are under-represented near or within genes encoding develop-mental regulators [218–220]. Similarly we hypothesizethat LTR/TE insertions predisposed to causing potentonco-exaptations at a high frequency would also be de-pleted by selective forces.In this review we have also presented two models thatmay explain such onco-exaptation events. These twomodels are not mutually exclusive but they do providealternative hypotheses by which TE-driven transcriptionmay be interpreted. This dichotomy is possibly best ex-emplified by the ERBB4 case (Fig. 1e) [129]. There aretwo LTR-derived promoters which result in aberrantERBB4 expression in ALCL. From the de-repressionmodel viewpoint, both LTR elements are grouped MLT1(MLT1C and MLT1H) and thus this group can be inter-preted as de-repressed. From the epigenetic evolutionmodel viewpoint, this is convergent evolution/selectionfor onco-exaptations involving ERBB4.Through application of the de-repression model, TE-derived transcripts could be used as a diagnostic markerin cancer. If the set of TE/LTR derived transcripts are adeterministic consequence of a given molecular state, byunderstanding which set of TEs correspond to whichmolecular state, it might be possible to assay cancersamples for functional molecular phenotypes. In HL forexample, CSF1R status is prognostically important [115]and this is dependent on the transcriptional state of asingle THE1B. HL also has a specific increase in THE1LTR transcription genome-wide (unpublished observa-tions). Thus, it’s reasonable to hypothesize that the prog-nostic power can be increased if the transcriptionalstatus of all THE1 LTRs is considered. A set of LTRs canthen be interpreted as an in situ ‘molecular sensor’ foraberrant NF-kB function in HL/B-cells for instance.The epigenetic evolution model proposes that LTR-driven transcripts can be interpreted as a set of epimuta-tions in cancer, similar to how oncogenic mutations areanalyzed. Genes that are recurrently (and independently)onco-exapted in multiple different tumors of the samecancer type may be a mark of selective pressure for ac-quiring that transcript. This is distinct from the more di-verse/noisy “passenger LTR” transcription occurringacross the genome. These active but “passenger LTRs”may be expressed to a high level within a single tumorpopulation due to epigenetic drift and population bot-tlenecks but would be more variable across different tu-mors. Thus analysis of recurrent and cancer-specificTE-derived transcripts may enrich for genes of signifi-cance to tumor biology.While we focused in this review on TE-initiated tran-scription in cancer, many of the concepts presented herecan be applied to other regulatory functions of TEs suchas enhancers, insulators, or repressors of transcription.Although less straightforward to measure, it is probablethat perturbations to such TE regulatory functions con-tribute to some malignancies. Furthermore, severalstudies have shown that TEs play substantial roles incryptic splicing in humans [221–223] and thus may bea further substrate of transcriptional innovation in can-cer, particularly since DNA methylation state can affectsplicing [224].Regardless of the underlying mechanism, onco-exaptation offers a tantalizing opportunity to modelevolutionary exaptation. Specifically, questions such as“How do TEs influence the rate of transcriptional/regu-latory change?” can be tested in cell culture experi-ments. As more studies that focus on regulatoryaberrations in cancer are performed in the comingyears, we predict that this phenomenon will become in-creasingly recognized as a significant force shapingtranscriptional innovation in cancer. Moreover, wepropose that studying such events will provide insightinto how TEs have contributed to reshaping transcrip-tional patterns during species evolution.AbbreviationsAFAP1-AS1: AFAP1 antisense RNA 1; ALCL: Anaplastic large-cell lymphoma;ALK: Anaplastic lymphoma kinase; BANCR: BRAF-regulated lncRNA 1;CAGE: Capped analysis of gene expression; CSFIR: Colony stimulating factorone receptor; DLBCL: Diffuse large B-cell lymphoma; ERBB4: Erb-b2 receptortyrosine kinase 4; ERV: Endogenous retrovirus; EST: Expressed sequence tag;ETV1: ETS variant 1; EVADR: Endogenous retroviral-associatedAdenocarcinoma RNA; FABP7: Fatty acid binding protein 7;HCC: Hepatocellular carcinoma; HL: Hodgkin lymphoma; HOST2: Humanovarian cancer specific transcript-2; HULC: Highly upregulated in liver cancer;IRF5: Interferon regulatory Factor 5; IRFE: Interferon regulatory factor-bindingelement; Linc-ROR: Long intergenic non-protein coding RNA, regulator ofreprogramming; LINE-1: L1: Long interspersed repeat-1; LncRNA: Long non-coding RNA; LTR: Long terminal repeat; MET: MET proto-oncogene, receptortyrosine kinase; OAT1B3: Organic anion transporting polypeptide 1B3;Babaian and Mager Mobile DNA  (2016) 7:24 Page 15 of 21SAMMSON: Survival associated mitochondrial melanoma specific oncogenicnon-coding RNA; SchLAP1: SWI/SNF complex antagonist associated withprostate cancer 1; SINE: Short interspersed element; SLCO1B3: Solute carrierorganic anion transporter family member 1B3; TCGA: The cancer genomeatlas; TE: Transposable element; TF: Transcription factor; TFPI-2: Tissue factorpathway inhibitor 2; TIS: Translation initiation site; TSS: Transcriptional startsite; UCA1: Urothelial cancer associated 1AcknowledgmentsWe thank Matt Lorincz and the anonymous reviewers for comments andhelpful suggestions on this manuscript. We apologize to colleagues andother researchers if we failed to cite relevant work on this subject.FundingWork on this topic in our laboratory has been funded by grants from theCanadian Institutes of Health Research (CIHR), the Natural Sciences andEngineering Research Council of Canada (NSERC), the Canadian CancerSociety and the Leukemia and Lymphoma Society of Canada, with coresupport provided by the BC Cancer Agency. AB is supported by astudentship award from NSERC.Availability of data and materialsData sharing not applicable as no datasets were generated or analyzedduring the current study.Authors’ contributionsAB and DLM wrote the manuscript and both authors approved the final version.Competing interestsThe authors declare that they have no competing interests.Consent for publicationNot applicable.Received: 1 September 2016 Accepted: 11 November 2016References1. International Human Genome Sequencing Consortium. Initial sequencingand analysis of the human genome. 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