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• W2018177575 abstract "LINE-1 (L1) retrotransposons are mobile genetic elements comprising ∼17% of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19 hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1%) donors presented germline retrotransposition events in the tumor suppressor mutated in colorectal cancers (MCC). MCC expression was ablated in each case, enabling oncogenic β-catenin/Wnt signaling. In the second example, suppression of tumorigenicity 18 (ST18) was activated by a tumor-specific L1 insertion. Experimental assays confirmed that the L1 interrupted a negative feedback loop by blocking ST18 repression of its enhancer. ST18 was also frequently amplified in HCC nodules from Mdr2−/− mice, supporting its assignment as a candidate liver oncogene. These proof-of-principle results substantiate L1-mediated retrotransposition as an important etiological factor in HCC. LINE-1 (L1) retrotransposons are mobile genetic elements comprising ∼17% of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19 hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1%) donors presented germline retrotransposition events in the tumor suppressor mutated in colorectal cancers (MCC). MCC expression was ablated in each case, enabling oncogenic β-catenin/Wnt signaling. In the second example, suppression of tumorigenicity 18 (ST18) was activated by a tumor-specific L1 insertion. Experimental assays confirmed that the L1 interrupted a negative feedback loop by blocking ST18 repression of its enhancer. ST18 was also frequently amplified in HCC nodules from Mdr2−/− mice, supporting its assignment as a candidate liver oncogene. These proof-of-principle results substantiate L1-mediated retrotransposition as an important etiological factor in HCC. L1 retrotransposons promote tumorigenesis in hepatocellular carcinoma (HCC) Germline L1 and Alu insertions in MCC activate β-catenin/Wnt signaling L1 mobilization in tumor cells accelerates transformation of the HCC genome A tumor-specific L1 insertion interrupts a negative feedback loop regulating ST18 Liver cancer accounts for 9% of all cancer deaths worldwide and 12% in developing countries (Jemal et al., 2011Jemal A. Bray F. Center M.M. Ferlay J. Ward E. Forman D. Global cancer statistics.CA Cancer J. Clin. 2011; 61: 69-90Crossref PubMed Scopus (30327) Google Scholar). Pathological inspection indicates hepatocellular carcinoma (HCC) in ∼80% of liver tumors, with infection by hepatitis B virus (HBV) and hepatitis C virus (HCV) being the most prevalent risk factors, followed by chronic alcoholism (Jemal et al., 2011Jemal A. Bray F. Center M.M. Ferlay J. Ward E. Forman D. Global cancer statistics.CA Cancer J. Clin. 2011; 61: 69-90Crossref PubMed Scopus (30327) Google Scholar; Perz et al., 2006Perz J.F. Armstrong G.L. Farrington L.A. Hutin Y.J. Bell B.P. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide.J. Hepatol. 2006; 45: 529-538Abstract Full Text Full Text PDF PubMed Scopus (1977) Google Scholar; Tateishi and Omata, 2012Tateishi R. Omata M. Hepatocellular carcinoma in 2011: genomics in hepatocellular carcinoma—a big step forward.Nat. Rev. Gastroenterol. Hepatol. 2012; 9: 69-70Crossref PubMed Scopus (10) Google Scholar). Although early detection and monitoring of patients with liver cirrhosis can substantially improve 5 year survival rates, progression to advanced HCC reduces average life expectancy to less than 8 months (Llovet et al., 2008Llovet J.M. Ricci S. Mazzaferro V. Hilgard P. Gane E. Blanc J.F. de Oliveira A.C. Santoro A. Raoul J.L. Forner A. et al.SHARP Investigators Study GroupSorafenib in advanced hepatocellular carcinoma.N. Engl. J. Med. 2008; 359: 378-390Crossref PubMed Scopus (9037) Google Scholar). As for other cancers, genome and exome resequencing have elucidated molecular pathways frequently perturbed in HCC (Guichard et al., 2012Guichard C. Amaddeo G. Imbeaud S. Ladeiro Y. Pelletier L. Maad I.B. Calderaro J. Bioulac-Sage P. Letexier M. Degos F. et al.Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.Nat. Genet. 2012; 44: 694-698Crossref PubMed Scopus (1037) Google Scholar; Tateishi and Omata, 2012Tateishi R. Omata M. Hepatocellular carcinoma in 2011: genomics in hepatocellular carcinoma—a big step forward.Nat. Rev. Gastroenterol. Hepatol. 2012; 9: 69-70Crossref PubMed Scopus (10) Google Scholar; Totoki et al., 2011Totoki Y. Tatsuno K. Yamamoto S. Arai Y. Hosoda F. Ishikawa S. Tsutsumi S. Sonoda K. Totsuka H. Shirakihara T. et al.High-resolution characterization of a hepatocellular carcinoma genome.Nat. Genet. 2011; 43: 464-469Crossref PubMed Scopus (240) Google Scholar), potentially enabling therapeutic intervention informed by the mutational signature of a given tumor. The capacity to catalog the full spectrum of genetic aberrations occurring in HCC is therefore of critical importance. LINE-1 (L1) retrotransposons are a major source of endogenous mutagenesis in humans (Burns and Boeke, 2012Burns K.H. Boeke J.D. Human transposon tectonics.Cell. 2012; 149: 740-752Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar; Levin and Moran, 2011Levin H.L. Moran J.V. Dynamic interactions between transposable elements and their hosts.Nat. Rev. Genet. 2011; 12: 615-627Crossref PubMed Scopus (392) Google Scholar). These mobile genetic elements utilize a “copy-and-paste” mechanism to retrotranspose to new genomic loci, with such success in germ cells that 500,000 L1 copies comprise ∼17% of the genome (Lander et al., 2001Lander E.S. Linton L.M. Birren B. Nusbaum C. Zody M.C. Baldwin J. Devon K. Dewar K. Doyle M. FitzHugh W. et al.International Human Genome Sequencing ConsortiumInitial sequencing and analysis of the human genome.Nature. 2001; 409: 860-921Crossref PubMed Scopus (17779) Google Scholar). Of these copies, only 80–100 are transposition competent, with distinct subsets of frequently active—or “hot”—L1s driving insertional mutagenesis in each individual genome (Beck et al., 2010Beck C.R. Collier P. Macfarlane C. Malig M. Kidd J.M. Eichler E.E. Badge R.M. Moran J.V. LINE-1 retrotransposition activity in human genomes.Cell. 2010; 141: 1159-1170Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar; Brouha et al., 2003Brouha B. Schustak J. Badge R.M. Lutz-Prigge S. Farley A.H. Moran J.V. Kazazian Jr., H.H. Hot L1s account for the bulk of retrotransposition in the human population.Proc. Natl. Acad. Sci. USA. 2003; 100: 5280-5285Crossref PubMed Scopus (740) Google Scholar). Retrotransposon insertions can profoundly alter gene structure and expression (Cordaux and Batzer, 2009Cordaux R. Batzer M.A. The impact of retrotransposons on human genome evolution.Nat. Rev. Genet. 2009; 10: 691-703Crossref PubMed Scopus (1094) Google Scholar; Faulkner et al., 2009Faulkner G.J. Kimura Y. Daub C.O. Wani S. Plessy C. Irvine K.M. Schroder K. Cloonan N. Steptoe A.L. Lassmann T. et al.The regulated retrotransposon transcriptome of mammalian cells.Nat. Genet. 2009; 41: 563-571Crossref PubMed Scopus (589) Google Scholar; Han et al., 2004Han J.S. Szak S.T. Boeke J.D. Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes.Nature. 2004; 429: 268-274Crossref PubMed Scopus (382) Google Scholar; Levin and Moran, 2011Levin H.L. Moran J.V. Dynamic interactions between transposable elements and their hosts.Nat. Rev. Genet. 2011; 12: 615-627Crossref PubMed Scopus (392) Google Scholar) and have been found in nearly 100 cases of disease (Faulkner, 2011Faulkner G.J. Retrotransposons: mobile and mutagenic from conception to death.FEBS Lett. 2011; 585: 1589-1594Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar; Hancks and Kazazian, 2012Hancks D.C. Kazazian Jr., H.H. Active human retrotransposons: variation and disease.Curr. Opin. Genet. Dev. 2012; 22: 191-203Crossref PubMed Scopus (424) Google Scholar). L1 activity is consequently suppressed in most somatic cells by methylation of a CpG island in the internal L1 promoter (Coufal et al., 2009Coufal N.G. Garcia-Perez J.L. Peng G.E. Yeo G.W. Mu Y. Lovci M.T. Morell M. O’Shea K.S. Moran J.V. Gage F.H. L1 retrotransposition in human neural progenitor cells.Nature. 2009; 460: 1127-1131Crossref PubMed Scopus (609) Google Scholar; Swergold, 1990Swergold G.D. Identification, characterization, and cell specificity of a human LINE-1 promoter.Mol. Cell. Biol. 1990; 10: 6718-6729Crossref PubMed Scopus (346) Google Scholar). By contrast, L1 is often hypomethylated in tumor cells, removing a key obstacle to retrotransposition (Levin and Moran, 2011Levin H.L. Moran J.V. Dynamic interactions between transposable elements and their hosts.Nat. Rev. Genet. 2011; 12: 615-627Crossref PubMed Scopus (392) Google Scholar). Despite this failure to repress L1 transcription, only a handful of L1 insertions had been found in human tumors until very recently (Liu et al., 1997Liu J. Nau M.M. Zucman-Rossi J. Powell J.I. Allegra C.J. Wright J.J. LINE-I element insertion at the t(11;22) translocation breakpoint of a desmoplastic small round cell tumor.Genes Chromosomes Cancer. 1997; 18: 232-239Crossref PubMed Scopus (34) Google Scholar; Miki et al., 1992Miki Y. Nishisho I. Horii A. Miyoshi Y. Utsunomiya J. Kinzler K.W. Vogelstein B. Nakamura Y. Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer.Cancer Res. 1992; 52: 643-645PubMed Google Scholar). High-throughput L1 integration site sequencing has since revealed 9 and 69 de novo L1 insertions, respectively, in lung and colorectal tumors (Iskow et al., 2010Iskow R.C. McCabe M.T. Mills R.E. Torene S. Pittard W.S. Neuwald A.F. Van Meir E.G. Vertino P.M. Devine S.E. Natural mutagenesis of human genomes by endogenous retrotransposons.Cell. 2010; 141: 1253-1261Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar; Solyom et al., 2012Solyom S. Ewing A.D. Rahrmann E.P. Doucet T. Nelson H.H. Burns M.B. Harris R.S. Sigmon D.F. Casella A. Erlanger B. et al.Extensive somatic L1 retrotransposition in colorectal tumors.Genome Res. 2012; 22: 2328-2338Crossref PubMed Scopus (192) Google Scholar), whereas cancer genome resequencing elucidated a further 183 tumor-specific L1 insertions in colorectal, ovarian, and prostate cancer (Lee et al., 2012Lee E. Iskow R. Yang L. Gokcumen O. Haseley P. Luquette 3rd, L.J. Lohr J.G. Harris C.C. Ding L. Wilson R.K. et al.Cancer Genome Atlas Research NetworkLandscape of somatic retrotransposition in human cancers.Science. 2012; 337: 967-971Crossref PubMed Scopus (514) Google Scholar). In this latter study, more than half of all insertions were found in a single colorectal tumor; the other individuals presented fewer than five tumor-specific L1 insertions on average. These data suggest L1 mobilization may be common in epithelial tumors, though the reasons for possible cell-of-origin restriction are currently unknown. Tumor-specific L1 retrotransposition has not previously been observed in HCC. For several reasons it is, however, a logical cancer in which to expect L1 mobilization. First, HCC is epithelial in origin. Second, HBV and HCV infection are common in HCC; viruses can suppress host defense factors, such as APOBEC proteins, that control retrotransposon activation. APOBEC3G has been shown, for instance, to inhibit both HBV replication and endogenous retrotransposition (Esnault et al., 2005Esnault C. Heidmann O. Delebecque F. Dewannieux M. Ribet D. Hance A.J. Heidmann T. Schwartz O. APOBEC3G cytidine deaminase inhibits retrotransposition of endogenous retroviruses.Nature. 2005; 433: 430-433Crossref PubMed Scopus (280) Google Scholar; Turelli et al., 2004Turelli P. Mangeat B. Jost S. Vianin S. Trono D. Inhibition of hepatitis B virus replication by APOBEC3G.Science. 2004; 303: 1829Crossref PubMed Scopus (391) Google Scholar). Third, liver inflammation precedes HCC and may, via cellular stress, stimulate retrotransposition (Fornace and Mitchell, 1986Fornace Jr., A.J. Mitchell J.B. Induction of B2 RNA polymerase III transcription by heat shock: enrichment for heat shock induced sequences in rodent cells by hybridization subtraction.Nucleic Acids Res. 1986; 14: 5793-5811Crossref PubMed Scopus (96) Google Scholar). Given these facts, we aimed to map L1 integration sites in HCC using retrotransposon capture sequencing (RC-seq) and assess their impact upon oncogenic and tumor suppressor pathways. To test the hypothesis that L1 mobilizes in HCC, we applied an updated RC-seq protocol to 19 HCC tumors and matched adjacent liver tissue that were confirmed positive for HBV or HCV infection (Table 1). An earlier RC-seq design (Baillie et al., 2011Baillie J.K. Barnett M.W. Upton K.R. Gerhardt D.J. Richmond T.A. De Sapio F. Brennan P.M. Rizzu P. Smith S. Fell M. et al.Somatic retrotransposition alters the genetic landscape of the human brain.Nature. 2011; 479: 534-537Crossref PubMed Scopus (510) Google Scholar) was modified to incorporate multiplex liquid-phase sequence capture (Figure 1A) using a refined probe pool (Table S1 available online) and a reduced insert size of ∼220 nt, which enabled high-confidence assembly of overlapping paired-end 150 nt reads (Figure 1B). This change simplified genomic alignment and, more importantly, enabled single-nucleotide resolution of retrotransposon integration sites (Figure 1C).Table 1Nonreference Genome Insertions Detected by RC-SeqDonorGenderVirusAgeGermline InsertionsPrivate Germline InsertionsValidated Tumor-Specific Insertions12MHCV652,082202315MHBV531,845216121MHCV512,019271029MHCV521,60244032MHBV731,681100033FHCV571,982234235FHCV781,78696042FHCV671,59443047MHBV611,58177248MHBV351,744212049MHCV681,64458060MHCV481,57033062MHBV331,750153070MHCV551,67382086FHBV561,70150089MHBV601,739163495MHBV541,773880106MHBV602,141480116MHBV621,532710F, female; M, male. Please see Tables S2 and S3 for supporting data and details. Open table in a new tab F, female; M, male. Please see Tables S2 and S3 for supporting data and details. After stringent filtering and mapping, an average of ∼2 million reads were retained per library with >95% identity to active L1, Alu, and SVA families, as well as the most recently active human LTR endogenous retroviruses (Table S2). Optimized sequence capture led to a 4-fold increase in reads aligned to nonreference genome L1s per library compared to previous RC-seq based on solid-phase arrays and similar sequencing depth (Baillie et al., 2011Baillie J.K. Barnett M.W. Upton K.R. Gerhardt D.J. Richmond T.A. De Sapio F. Brennan P.M. Rizzu P. Smith S. Fell M. et al.Somatic retrotransposition alters the genetic landscape of the human brain.Nature. 2011; 479: 534-537Crossref PubMed Scopus (510) Google Scholar). The improved resolution of RC-seq also allowed us to discriminate a required minimum of two unique amplicons in support of any nonreference genome insertion (see Extended Experimental Procedures). A total of 7,689 nonreference genome insertions were detected in 19 tumor (T) samples and 19 matched nontumor (NT) liver samples. Of these, we annotated 7,644 as putatively germline (Table S3) because of their presence in (1) databases of retrotransposon-induced polymorphisms (Beck et al., 2010Beck C.R. Collier P. Macfarlane C. Malig M. Kidd J.M. Eichler E.E. Badge R.M. Moran J.V. LINE-1 retrotransposition activity in human genomes.Cell. 2010; 141: 1159-1170Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar; Ewing and Kazazian, 2010Ewing A.D. Kazazian Jr., H.H. High-throughput sequencing reveals extensive variation in human-specific L1 content in individual human genomes.Genome Res. 2010; 20: 1262-1270Crossref PubMed Scopus (234) Google Scholar; Iskow et al., 2010Iskow R.C. McCabe M.T. Mills R.E. Torene S. Pittard W.S. Neuwald A.F. Van Meir E.G. Vertino P.M. Devine S.E. Natural mutagenesis of human genomes by endogenous retrotransposons.Cell. 2010; 141: 1253-1261Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar; Wang et al., 2006Wang J. Song L. Grover D. Azrak S. Batzer M.A. Liang P. dbRIP: a highly integrated database of retrotransposon insertion polymorphisms in humans.Hum. Mutat. 2006; 27: 323-329Crossref PubMed Scopus (144) Google Scholar), (2) pre-existing insertions annotated by pooled blood RC-seq (Baillie et al., 2011Baillie J.K. Barnett M.W. Upton K.R. Gerhardt D.J. Richmond T.A. De Sapio F. Brennan P.M. Rizzu P. Smith S. Fell M. et al.Somatic retrotransposition alters the genetic landscape of the human brain.Nature. 2011; 479: 534-537Crossref PubMed Scopus (510) Google Scholar), (3) multiple individuals, or (4) nontumor liver. L1, Alu, SVA, and LTR-flanked retrotransposons comprised 13.5%, 81.8%, 4.3%, and 0.4% of germline insertions, respectively. As expected, L1-Ta and L1-pre-Ta (99.3%) and AluY (99.7%) were the main L1 and Alu subfamilies active in germ cells (Mills et al., 2007Mills R.E. Bennett E.A. Iskow R.C. Devine S.E. Which transposable elements are active in the human genome?.Trends Genet. 2007; 23: 183-191Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar). A total of 2,241 germline insertions were found in only one individual each (Table 1 and Table S3) and were not annotated by the aforementioned retrotransposon polymorphism databases, suggesting that these were private or rare mutations or, alternatively, had occurred in early development (Garcia-Perez et al., 2007Garcia-Perez J.L. Marchetto M.C. Muotri A.R. Coufal N.G. Gage F.H. O’Shea K.S. Moran J.V. LINE-1 retrotransposition in human embryonic stem cells.Hum. Mol. Genet. 2007; 16: 1569-1577Crossref PubMed Scopus (169) Google Scholar; Kano et al., 2009Kano H. Godoy I. Courtney C. Vetter M.R. Gerton G.L. Ostertag E.M. Kazazian Jr., H.H. L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism.Genes Dev. 2009; 23: 1303-1312Crossref PubMed Scopus (283) Google Scholar). RC-seq detected 1,489 (66.4%) insertions at both their 5′ and 3′ ends, enabling us to model the characteristic sequence features of L1-mediated retrotransposition. Without any additional sequencing, we were able to analyze insertions for the presence of target site duplications (TSDs), an L1-endonuclease recognition motif (Jurka, 1997Jurka J. Sequence patterns indicate an enzymatic involvement in integration of mammalian retroposons.Proc. Natl. Acad. Sci. USA. 1997; 94: 1872-1877Crossref PubMed Scopus (426) Google Scholar), and a polyA tail (Figures 2A and 2B ). These features consistently resembled target-primed reverse transcription (TPRT) for L1, Alu, and SVA, again illustrating the primary retrotransposition mechanism in germ cells (Cost et al., 2002Cost G.J. Feng Q. Jacquier A. Boeke J.D. Human L1 element target-primed reverse transcription in vitro.EMBO J. 2002; 21: 5899-5910Crossref PubMed Scopus (379) Google Scholar; Jurka, 1997Jurka J. Sequence patterns indicate an enzymatic involvement in integration of mammalian retroposons.Proc. Natl. Acad. Sci. USA. 1997; 94: 1872-1877Crossref PubMed Scopus (426) Google Scholar). We also identified 160 previously undetected full-length (>99.9%) L1 copies, including 115 with paired 5′/3′ detection (Figure 2C; Table S4) and 82 each found in a single donor only. All were annotated as L1-Ta or pre-Ta. These potentially “hot” L1s added to a recent cohort of full-length L1 insertions found in six geographically diverse individuals via fosmid screening and sequencing (Beck et al., 2010Beck C.R. Collier P. Macfarlane C. Malig M. Kidd J.M. Eichler E.E. Badge R.M. Moran J.V. LINE-1 retrotransposition activity in human genomes.Cell. 2010; 141: 1159-1170Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar). Of 68 L1 insertions reported by Beck et al., 2010Beck C.R. Collier P. Macfarlane C. Malig M. Kidd J.M. Eichler E.E. Badge R.M. Moran J.V. LINE-1 retrotransposition activity in human genomes.Cell. 2010; 141: 1159-1170Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar, we detected 49 (72.1%), including 15/18 (83.3%) with an allelic frequency >5%. Of the 49 insertions common to both studies, 46 (93.9%) were base-pair identical in genomic position. These results confirm strong agreement between RC-seq and the conservative fosmid-based approach of Beck et al., 2010Beck C.R. Collier P. Macfarlane C. Malig M. Kidd J.M. Eichler E.E. Badge R.M. Moran J.V. LINE-1 retrotransposition activity in human genomes.Cell. 2010; 141: 1159-1170Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar. Each individual genome contained on average 244 nonreference genome L1 insertions, a figure 60% and 80% higher, respectively, than recent L1 insertion site sequencing on cell lines (Ewing and Kazazian, 2010Ewing A.D. Kazazian Jr., H.H. High-throughput sequencing reveals extensive variation in human-specific L1 content in individual human genomes.Genome Res. 2010; 20: 1262-1270Crossref PubMed Scopus (234) Google Scholar) and single cells (Evrony et al., 2012Evrony G.D. Cai X. Lee E. Hills L.B. Elhosary P.C. Lehmann H.S. Parker J.J. Atabay K.D. Gilmore E.C. Poduri A. et al.Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain.Cell. 2012; 151: 483-496Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar). Therefore, to assess the RC-seq false-positive rate, we randomly selected 200 germline insertions (173 Alu, 14 L1, 11 SVA, and 2 LTR) for site-specific PCR validation (Table S5). Of these, we confirmed 197 (98.5%). The remaining three insertions (2 SVA and 1 Alu) occurred in repetitive genomic regions and were detected by multiple unique reads in at least ten different samples each, indicating that these may have represented PCR false negatives. These comparisons and experiments together demonstrate the sensitive and accurate mapping of bona fide retrotransposition events by RC-seq and further highlight ongoing L1 retrotransposition in the global human population (Beck et al., 2010Beck C.R. Collier P. Macfarlane C. Malig M. Kidd J.M. Eichler E.E. Badge R.M. Moran J.V. LINE-1 retrotransposition activity in human genomes.Cell. 2010; 141: 1159-1170Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar; Ewing and Kazazian, 2010Ewing A.D. Kazazian Jr., H.H. High-throughput sequencing reveals extensive variation in human-specific L1 content in individual human genomes.Genome Res. 2010; 20: 1262-1270Crossref PubMed Scopus (234) Google Scholar; Huang et al., 2010Huang C.R. Schneider A.M. Lu Y. Niranjan T. Shen P. Robinson M.A. Steranka J.P. Valle D. Civin C.I. Wang T. et al.Mobile interspersed repeats are major structural variants in the human genome.Cell. 2010; 141: 1171-1182Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar; Iskow et al., 2010Iskow R.C. McCabe M.T. Mills R.E. Torene S. Pittard W.S. Neuwald A.F. Van Meir E.G. Vertino P.M. Devine S.E. Natural mutagenesis of human genomes by endogenous retrotransposons.Cell. 2010; 141: 1253-1261Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar). To assess the potential tumorigenic consequences of the identified nonreference genome insertions, we selected and validated, by insertion site PCR, 31 L1, Alu, and SVA insertions in genes generally implicated to play a causal role in cancer (Futreal et al., 2004Futreal P.A. Coin L. Marshall M. Down T. Hubbard T. Wooster R. Rahman N. Stratton M.R. A census of human cancer genes.Nat. Rev. Cancer. 2004; 4: 177-183Crossref PubMed Scopus (2418) Google Scholar) or specifically in HCC (Guichard et al., 2012Guichard C. Amaddeo G. Imbeaud S. Ladeiro Y. Pelletier L. Maad I.B. Calderaro J. Bioulac-Sage P. Letexier M. Degos F. et al.Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.Nat. Genet. 2012; 44: 694-698Crossref PubMed Scopus (1037) Google Scholar), including L1 insertions in the proto-oncogene ALK and the tumor suppressor FHIT (Table S5). Quantitative RT-PCR indicated, however, that 28/31 of these germline insertions did not significantly perturb host gene expression in tumor or nontumor liver versus control liver from five unaffected individuals (data not shown). Strikingly, the three remaining insertions all coincided with strong inhibition of the tumor suppressor mutated in colorectal cancers (MCC) (Higgins et al., 2007Higgins M.E. Claremont M. Major J.E. Sander C. Lash A.E. CancerGenes: a gene selection resource for cancer genome projects.Nucleic Acids Res. 2007; 35: D721-D726Crossref PubMed Scopus (145) Google Scholar). MCC is expressed in liver (Senda et al., 1999Senda T. Matsumine A. Yanai H. Akiyama T. Localization of MCC (mutated in colorectal cancer) in various tissues of mice and its involvement in cell differentiation.J. Histochem. Cytochem. 1999; 47: 1149-1158Crossref PubMed Scopus (12) Google Scholar) and regulates the oncogenic β-catenin/Wnt signaling pathway frequently activated in HCC (Fukuyama et al., 2008Fukuyama R. Niculaita R. Ng K.P. Obusez E. Sanchez J. Kalady M. Aung P.P. Casey G. Sizemore N. Mutated in colorectal cancer, a putative tumor suppressor for serrated colorectal cancer, selectively represses beta-catenin-dependent transcription.Oncogene. 2008; 27: 6044-6055Crossref PubMed Scopus (66) Google Scholar; Guichard et al., 2012Guichard C. Amaddeo G. Imbeaud S. Ladeiro Y. Pelletier L. Maad I.B. Calderaro J. Bioulac-Sage P. Letexier M. Degos F. et al.Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.Nat. Genet. 2012; 44: 694-698Crossref PubMed Scopus (1037) Google Scholar; Totoki et al., 2011Totoki Y. Tatsuno K. Yamamoto S. Arai Y. Hosoda F. Ishikawa S. Tsutsumi S. Sonoda K. Totsuka H. Shirakihara T. et al.High-resolution characterization of a hepatocellular carcinoma genome.Nat. Genet. 2011; 43: 464-469Crossref PubMed Scopus (240) Google Scholar). In vitro experiments have established that siRNA knockdown of MCC mRNA dramatically increases β-catenin (CTNNB1) expression, whereas MCC overexpression inhibits cellular proliferation (Fukuyama et al., 2008Fukuyama R. Niculaita R. Ng K.P. Obusez E. Sanchez J. Kalady M. Aung P.P. Casey G. Sizemore N. Mutated in colorectal cancer, a putative tumor suppressor for serrated colorectal cancer, selectively represses beta-catenin-dependent transcription.Oncogene. 2008; 27: 6044-6055Crossref PubMed Scopus (66) Google Scholar; Matsumine et al., 1996Matsumine A. Senda T. Baeg G.H. Roy B.C. Nakamura Y. Noda M. Toyoshima K. Akiyama T. MCC, a cytoplasmic protein that blocks cell cycle progression from the G0/G1 to S phase.J. Biol. Chem. 1996; 271: 10341-10346Crossref PubMed Scopus (35) Google Scholar). MCC is also an intriguing HCC candidate gene because of its genomic proximity to APC, a major tumor suppressor mutated in familial adenomatous polyposis preceding colorectal cancer (Groden et al., 1991Groden J. Thliveris A. Samowitz W. Carlson M. Gelbert L. Albertsen H. Joslyn G. Stevens J. Spirio L. Robertson M. et al.Identification and characterization of the familial adenomatous polyposis coli gene.Cell. 1991; 66: 589-600Abstract Full Text PDF PubMed Scopus (2402) Google Scholar; Kinzler et al., 1991Kinzler K.W. Nilbert M.C. Vogelstein B. Bryan T.M. Levy D.B. Smith K.J. Preisinger A.C. Hamilton S.R. Hedge P. Markham A. et al.Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers.Science. 1991; 251: 1366-1370Crossref PubMed Scopus (635) Google Scholar). It is important to note that mutated APC occurs in <2% of HCC cases versus >60% of colorectal carcinomas (Guichard et al., 2012Guichard C. Amaddeo G. Imbeaud S. Ladeiro Y. Pelletier L. Maad I.B. Calderaro J. Bioulac-Sage P. Letexier M. Degos F. et al.Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.Nat. Genet. 2012; 44: 694-698Crossref PubMed Scopus (1037) Google Scholar; Powell et al., 1992Powell S.M. Zilz N. Beazer-Barclay Y. Bryan T.M. Hamilton S.R. Thibodeau S.N. Vogelstein B. Kinzler K.W. APC mutations occur early during colorectal tumorigenesis.Nature. 1992; 359: 235-237Crossref PubMed Scopus (1677) Google Scholar). We therefore hypothesized that germline retrotransposition events specifically inhibited MCC tumor suppressor function in liver. To test this prediction, we assessed the impact of each MCC mutation upon MCC, APC, and CTNNB1 expression. Three germline retrotransposon insertions were found in MCC. The first of these, labeled MCC-L1-α, comprised a 5.3 kb L1-Ta oriented in sense to MCC in donors 70 and 95 (Figure 3A). Another L1-Ta, labeled MCC-L1-β, was full-length (6 kb), occurred at a different genomic position in donor 116, and was oriented antisense to MCC (Figure 3B). Finally, in donor 33, we found an AluY (MCC-Alu; Figure 3C) inserted in an ENCODE-delineated enhancer (Thurman et al., 2012Thurman R.E. Rynes E. Humbert R. Vierstra J. Maurano M.T. Haugen E. Sheffield N.C. Stergachis A.B. Wang H. Vernot B. et al.The accessible chromatin landscape of the human genome.Nature. 2012; 489: 75-82Crossref PubMed Scopus (1801) Google Scholar). Insertion site PCR revealed that MCC-L1-α was heterozygous in donor 70 and homozygous (or possibly hemizygous) in donor 95, whereas MCC-L1-β and MCC-Alu were heterozygo" @default.
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• W2018177575 title "Endogenous Retrotransposition Activates Oncogenic Pathways in Hepatocellular Carcinoma" @default.
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• W2018177575 doi "https://doi.org/10.1016/j.cell.2013.02.032" @default.
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