Friday, December 12, 2025
No menu items!
HomeNatureUncovering the role of LINE-1 in the evolution of lung adenocarcinoma

Uncovering the role of LINE-1 in the evolution of lung adenocarcinoma

  • Yates, L. R. & Campbell, P. J. Evolution of the cancer genome. Nat. Rev. Genet. 13, 795–806 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jamal-Hanjani, M. et al. Tracking the evolution of non-small-cell lung cancer. N. Engl. J. Med. 376, 2109–2121 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Alexandrov, L. B. et al. Mutational signatures R. Science 354, 618–622 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yang, P., Wang, Y. & Macfarlan, T. S. The role of KRAB-ZFPs in transposable element repression and mammalian evolution. Trends Genet. 33, 871–881 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhang, Y. et al. Global variations in lung cancer incidence by histological subtype in 2020: a population-based study. Lancet Oncol. 24, 1206–1218 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Gerstung, M. et al. The evolutionary history of 2,658 cancers. Nature 578, 122–128 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Frankell, A. M. et al. The evolution of lung cancer and impact of subclonal selection in TRACERx. Nature 616, 525–533 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Burns, K. H. Transposable elements in cancer. Nat. Rev. Cancer 17, 415–424 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rodriguez-Martin, B. et al. Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition. Nat. Genet. 52, 306–319 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mendez-Dorantes, C. et al. Chromosomal rearrangements and instability caused by the LINE-1 retrotransposon. Preprint at bioRxiv https://doi.org/10.1101/2024.12.14.628481 (2024).

  • Rodić, N. et al. Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma. Nat. Med. 21, 1060–1064 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Nguyen, T. H. M. et al. L1 retrotransposon heterogeneity in ovarian tumor cell evolution. Cell Rep. 23, 3730–3740 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhang, T. et al. Genomic and evolutionary classification of lung cancer in never smokers. Nat. Genet. 53, 1348–1359 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Landi, M. T. et al. Tracing lung cancer risk factors through mutational signatures in never-smokers. Am. J. Epidemiol. 190, 962–976 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Zhu, B. et al. The genomic and epigenomic evolutionary history of papillary renal cell carcinomas. Nat. Commun. 11, 3096 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Senkin, S. et al. Geographic variation of mutagenic exposures in kidney cancer genomes. Nature 629, 910–918 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Díaz-Gay, M. et al. The mutagenic forces shaping the genomes of lung cancer in never smokers. Nature 644, 133–144 (2025).

    Article 
    PubMed 

    Google Scholar
     

  • McGranahan, N. et al. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Sci. Transl. Med. 7, 283ra54 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Otlu, B. et al. Topography of mutational signatures in human cancer. Cell Rep. 42, 112930 (2023).

  • Stamatoyannopoulos, J. A. et al. Human mutation rate associated with DNA replication timing. Nat. Genet. 41, 393–395 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Whitfield, M. L., George, L. K., Grant, G. D. & Perou, C. M. Common markers of proliferation. Nat. Rev. Cancer 6, 99–106 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Emami Nejad, A. et al. The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment. Cancer Cell Int. 21, 62 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bhandari, V., Li, C. H., Bristow, R. G., Boutros, P. C. & PCAWG Consortium. Divergent mutational processes distinguish hypoxic and normoxic tumours. Nat. Commun. 11, 737 (2020).

  • Liu, N. et al. Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators. Nature 553, 228–232 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li, X. et al. LINE-1 transcription activates long-range gene expression. Nat. Genet. 56, 1494–1502 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Scott, E. C. & Devine, S. E. The role of somatic L1 retrotransposition in human cancers. Viruses 9, 131 (2017).

  • Tubio, J. M. C. et al. Mobile DNA in cancer. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science 345, 1251343 (2014).

    Article 
    PubMed 

    Google Scholar
     

  • McKerrow, W. et al. LINE-1 expression in cancer correlates with p53 mutation, copy number alteration, and S phase checkpoint. Proc. Natl Acad. Sci. USA 119, e2115999119 (2022).

  • Kazazian, H. H. Jr & Moran, J. V. Mobile DNA in health and disease. N. Engl. J. Med. 377, 361–370 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Petljak, M. et al. Characterizing mutational signatures in human cancer cell lines reveals episodic APOBEC mutagenesis. Cell 176, 1282–1294 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nam, C. H. et al. Widespread somatic L1 retrotransposition in normal colorectal epithelium. Nature 617, 540–547 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Levin, H. L. & Moran, J. V. Dynamic interactions between transposable elements and their hosts. Nat. Rev. Genet. 12, 615–627 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gasior, S. L., Wakeman, T. P., Xu, B. & Deininger, P. L. The human LINE-1 retrotransposon creates DNA double-strand breaks. J. Mol. Biol. 357, 1383–1393 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Morrish, T. A. et al. DNA repair mediated by endonuclease-independent LINE-1 retrotransposition. Nat. Genet. 31, 159–165 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Farkash, E. A. & Luning Prak, E. T. DNA damage and L1 retrotransposition. J. Biomed. Biotechnol. 2006, 37285 (2006).

    PubMed 

    Google Scholar
     

  • Suzuki, J. et al. Genetic evidence that the non-homologous end-joining repair pathway is involved in LINE retrotransposition. PLoS Genet. 5, e1000461 (2009).

    Article 
    PubMed 

    Google Scholar
     

  • Baldwin, E. T. et al. Structures, functions and adaptations of the human LINE-1 ORF2 protein. Nature 626, 194–206 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Freeman, B. et al. Analysis of epigenetic features characteristic of L1 loci expressed in human cells. Nucleic Acids Res. 50, 1888–1907 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rodgers, K. & McVey, M. Error-prone repair of DNA double-strand breaks. J. Cell. Physiol. 231, 15–24 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wangsri, S., Subbalekha, K., Kitkumthorn, N. & Mutirangura, A. Patterns and possible roles of LINE-1 methylation changes in smoke-exposed epithelia. PLoS ONE 7, e45292 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Stueve, T. R. et al. Epigenome-wide analysis of DNA methylation in lung tissue shows concordance with blood studies and identifies tobacco smoke-inducible enhancers. Hum. Mol. Genet. 26, 3014–3027 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Caliri, A. W., Caceres, A., Tommasi, S. & Besaratinia, A. Hypomethylation of LINE-1 repeat elements and global loss of DNA hydroxymethylation in vapers and smokers. Epigenetics 15, 816–829 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Camila, B. et al. Genotoxicity and hypomethylation of LINE-1 induced by electronic cigarettes. Ecotoxicol. Environ. Saf. 256, 114900 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Joehanes, R. et al. Epigenetic signatures of cigarette smoking. Circ. Cardiovasc. Genet. 9, 436–447 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Imbeault, M., Helleboid, P.-Y. & Trono, D. KRAB zinc-finger proteins contribute to the evolution of gene regulatory networks. Nature 543, 550–554 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Han, G. et al. An atlas of epithelial cell states and plasticity in lung adenocarcinoma. Nature 627, 656–663 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Long, E. et al. Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes. Nat. Commun. 15, 7995 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rosspopoff, O. & Trono, D. Take a walk on the KRAB side. Trends Genet. 39, 844–857 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hill, W. et al. Lung adenocarcinoma promotion by air pollutants. Nature 616, 159–167 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Haga, Y. et al. Whole-genome sequencing reveals the molecular implications of the stepwise progression of lung adenocarcinoma. Nat. Commun. 14, 8375 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huang, Z. et al. Single-cell analysis of somatic mutations in human bronchial epithelial cells in relation to aging and smoking. Nat. Genet. 54, 492–498 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Colom, B. et al. Mutant clones in normal epithelium outcompete and eliminate emerging tumours. Nature 598, 510–514 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jardim, D. L., Goodman, A., de Melo Gagliato, D. & Kurzrock, R. The challenges of tumor mutational burden as an immunotherapy biomarker. Cancer Cell 39, 154–173 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Klein, S. L. & Flanagan, K. L. Sex differences in immune responses. Nat. Rev. Immunol. 16, 626–638 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Vaz, M. et al. Chronic cigarette smoke-induced epigenomic changes precede sensitization of bronchial epithelial cells to single-step transformation by KRAS mutations. Cancer Cell 32, 360–376 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mengs, U. Tumour induction in mice following exposure to aristolochic acid. Arch. Toxicol. 61, 504–505 (1988).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ambatipudi, S. et al. Tobacco smoking-associated genome-wide DNA methylation changes in the EPIC study. Epigenomics 8, 599–618 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kobayashi, S. et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352, 786–792 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Shah, N. M. et al. Pan-cancer analysis identifies tumor-specific antigens derived from transposable elements. Nat. Genet. 55, 631–639 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bergmann, E. A., Chen, B.-J., Arora, K., Vacic, V. & Zody, M. C. Conpair: concordance and contamination estimator for matched tumor-normal pairs. Bioinformatics 32, 3196–3198 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pedersen, B. S. et al. Somalier: rapid relatedness estimation for cancer and germline studies using efficient genome sketches. Genome Med. 12, 62 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nik-Zainal, S. et al. The life history of 21 breast cancers. Cell 149, 994–1007 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dentro, S. C. et al. Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes. Cell 184, 2239–2254 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sadedin, S. P. & Oshlack, A. Bazam: a rapid method for read extraction and realignment of high-throughput sequencing data. Genome Biol. 20, 78 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Martínez-Jiménez, F. et al. A compendium of mutational cancer driver genes. Nat. Rev. Cancer 20, 555–572 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Yuan, K., Macintyre, G., Liu, W., PCAWG-11 Working Group & Markowetz, F. Ccube: a fast and robust method for estimating cancer cell fractions. Preprint at bioRxiv https://doi.org/10.1101/484402 (2018).

  • Yang, L. et al. Diverse mechanisms of somatic structural variations in human cancer genomes. Cell 153, 919–929 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chen, X. et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics 32, 1220–1222 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Muiños, F., Martínez-Jiménez, F., Pich, O., Gonzalez-Perez, A. & Lopez-Bigas, N. In silico saturation mutagenesis of cancer genes. Nature 596, 428–432 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Chakravarty, D. et al. OncoKB: a precision oncology knowledge base. JCO Precis. Oncol. 1, 1–16 (2017).

  • Bailey, M. H. et al. Comprehensive characterization of cancer driver genes and mutations. Cell 173, 371–385 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cheng, J. et al. Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science 381, eadg7492 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bergstrom, E. N. et al. SigProfilerMatrixGenerator: a tool for visualizing and exploring patterns of small mutational events. BMC Genom. 20, 685 (2019).

    Article 

    Google Scholar
     

  • Islam, S. M. A. et al. Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor. Cell Genom. 2, 100179 (2022).

  • Sondka, Z. et al. COSMIC: a curated database of somatic variants and clinical data for cancer. Nucleic Acids Res. 52, D1210–D1217 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Díaz-Gay, M. et al. Assigning mutational signatures to individual samples and individual somatic mutations with SigProfilerAssignment. Bioinformatics 39, btad756 (2023).

  • Degasperi, A. et al. Substitution mutational signatures in whole-genome-sequenced cancers in the UK population. Science 376, abl9283 (2022).

  • Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).

    Article 

    Google Scholar
     

  • Grossman, R. L. et al. Toward a shared vision for cancer genomic data. N. Engl. J. Med. 375, 1109–1112 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Putri, G. H., Anders, S., Pyl, P. T., Pimanda, J. E. & Zanini, F. Analysing high-throughput sequencing data in Python with HTSeq 2.0. Bioinformatics 38, 2943–2945 (2022).

  • Zhang, Y., Parmigiani, G. & Johnson, W. E. ComBat-seq: batch effect adjustment for RNA-seq count data. NAR Genom. Bioinform. 2, lqaa078 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liberzon, A. et al. Molecular signatures database (MSigDB) 3.0. Bioinformatics 27, 1739–1740 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li, T. et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 48, W509–W514 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • de Tribolet-Hardy, J. et al. Genetic features and genomic targets of human KRAB-zinc finger proteins. Genome Res. 33, 1409–1423 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Del Toro, N. et al. The IntAct database: efficient access to fine-grained molecular interaction data. Nucleic Acids Res. 50, D648–D653 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Oleksiewicz, U. et al. TRIM28 and interacting KRAB-ZNFs control self-renewal of human pluripotent stem cells through epigenetic repression of pro-differentiation genes. Stem Cell Rep. 9, 2065–2080 (2017).

    Article 
    CAS 

    Google Scholar
     

  • McKerrow, W. & Fenyö, D. L1EM: a tool for accurate locus specific LINE-1 RNA quantification. Bioinformatics 36, 1167–1173 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Reyes-Gopar, H. et al. A single-cell transposable element atlas of human cell identity. Cell Rep. Methods 5, 101086 (2025).

  • Müller, F. et al. RnBeads 2.0: comprehensive analysis of DNA methylation data. Genome Biol. 20, 55 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Leek, J. T., Johnson, W. E., Parker, H. S., Jaffe, A. E. & Storey, J. D. The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics 28, 882–883 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kawaguchi, S., Higasa, K., Shimizu, M., Yamada, R. & Matsuda, F. HLA-HD: an accurate HLA typing algorithm for next-generation sequencing data. Hum. Mutat. 38, 788–797 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Reynisson, B., Alvarez, B., Paul, S., Peters, B. & Nielsen, M. NetMHCpan-4.1 and NetMHCIIpan-4.0: improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data. Nucleic Acids Res. 48, W449–W454 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Schenck, R. O., Lakatos, E., Gatenbee, C., Graham, T. A. & Anderson, A. R. A. NeoPredPipe: high-throughput neoantigen prediction and recognition potential pipeline. BMC Bioinform. 20, 264 (2019).

    Article 

    Google Scholar
     

  • Thorsson, V. et al. The immune landscape of cancer. Immunity 48, 812–830 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Buffa, F. M., Harris, A. L., West, C. M. & Miller, C. J. Large meta-analysis of multiple cancers reveals a common, compact and highly prognostic hypoxia metagene. Br. J. Cancer 102, 428–435 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Winter, S. C. et al. Relation of a hypoxia metagene derived from head and neck cancer to prognosis of multiple cancers. Cancer Res. 67, 3441–3449 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ragnum, H. B. et al. The tumour hypoxia marker pimonidazole reflects a transcriptional programme associated with aggressive prostate cancer. Br. J. Cancer 112, 382–390 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Elvidge, G. P. et al. Concordant regulation of gene expression by hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: the role of HIF-1α, HIF-2α, and other pathways. J. Biol. Chem. 281, 15215–15226 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sørensen, B. S., Toustrup, K., Horsman, M. R., Overgaard, J. & Alsner, J. Identifying pH independent hypoxia induced genes in human squamous cell carcinomas in vitro. Acta Oncol. 49, 895–905 (2010).

    Article 
    PubMed 

    Google Scholar
     

  • RELATED ARTICLES

    Most Popular

    Recent Comments