Landscape of Somatic Retrotransposition in Human Cancers

Overview

Journal Science

Specialty Science

Date 2012 Jun 30

PMID 22745252

Citations 444

Authors

Eunjung Lee

Rebecca Iskow

Lixing Yang

Omer Gokcumen

Psalm Haseley

Lovelace J Luquette 3rd

Jens G Lohr

Christopher C Harris

Li Ding

Richard K Wilson

David A Wheeler

Richard A Gibbs

Raju Kucherlapati

Charles Lee

Peter V Kharchenko

Peter J Park

Affiliations

Soon will be listed here.

Abstract

Transposable elements (TEs) are abundant in the human genome, and some are capable of generating new insertions through RNA intermediates. In cancer, the disruption of cellular mechanisms that normally suppress TE activity may facilitate mutagenic retrotranspositions. We performed single-nucleotide resolution analysis of TE insertions in 43 high-coverage whole-genome sequencing data sets from five cancer types. We identified 194 high-confidence somatic TE insertions, as well as thousands of polymorphic TE insertions in matched normal genomes. Somatic insertions were present in epithelial tumors but not in blood or brain cancers. Somatic L1 insertions tend to occur in genes that are commonly mutated in cancer, disrupt the expression of the target genes, and are biased toward regions of cancer-specific DNA hypomethylation, highlighting their potential impact in tumorigenesis.

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References

Prak E, Kazazian Jr H . Mobile elements and the human genome. Nat Rev Genet. 2001; 1(2):134-44. DOI: 10.1038/35038572. View

Yang N, Kazazian Jr H . L1 retrotransposition is suppressed by endogenously encoded small interfering RNAs in human cultured cells. Nat Struct Mol Biol. 2006; 13(9):763-71. DOI: 10.1038/nsmb1141. View

Hastings P, Ira G, Lupski J . A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet. 2009; 5(1):e1000327. PMC: 2621351. DOI: 10.1371/journal.pgen.1000327. View

Ewing A, Kazazian Jr H . Whole-genome resequencing allows detection of many rare LINE-1 insertion alleles in humans. Genome Res. 2010; 21(6):985-90. PMC: 3106331. DOI: 10.1101/gr.114777.110. View

Maksakova I, Mager D, Reiss D . Keeping active endogenous retroviral-like elements in check: the epigenetic perspective. Cell Mol Life Sci. 2008; 65(21):3329-47. PMC: 11131743. DOI: 10.1007/s00018-008-8494-3. View

Miki Y, Nishisho I, Horii A, Miyoshi Y, Utsunomiya J, Kinzler K . Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. Cancer Res. 1992; 52(3):643-5. View

Slotkin R, Martienssen R . Transposable elements and the epigenetic regulation of the genome. Nat Rev Genet. 2007; 8(4):272-85. DOI: 10.1038/nrg2072. View

Ewing A, Kazazian Jr H . High-throughput sequencing reveals extensive variation in human-specific L1 content in individual human genomes. Genome Res. 2010; 20(9):1262-70. PMC: 2928504. DOI: 10.1101/gr.106419.110. View

Zheng H, Ying H, Wiedemeyer R, Yan H, Quayle S, Ivanova E . PLAGL2 regulates Wnt signaling to impede differentiation in neural stem cells and gliomas. Cancer Cell. 2010; 17(5):497-509. PMC: 2900858. DOI: 10.1016/j.ccr.2010.03.020. View

10.

Molaro A, Hodges E, Fang F, Song Q, McCombie W, Hannon G . Sperm methylation profiles reveal features of epigenetic inheritance and evolution in primates. Cell. 2011; 146(6):1029-41. PMC: 3205962. DOI: 10.1016/j.cell.2011.08.016. View

11.

Dickinson R, Fegan K, Ren X, Hillier S, Duncan W . Glucocorticoid regulation of SLIT/ROBO tumour suppressor genes in the ovarian surface epithelium and ovarian cancer cells. PLoS One. 2011; 6(11):e27792. PMC: 3223191. DOI: 10.1371/journal.pone.0027792. View

12.

Izumi H, Inoue J, Yokoi S, Hosoda H, Shibata T, Sunamori M . Frequent silencing of DBC1 is by genetic or epigenetic mechanisms in non-small cell lung cancers. Hum Mol Genet. 2005; 14(8):997-1007. DOI: 10.1093/hmg/ddi092. View

13.

Iskow R, McCabe M, Mills R, Torene S, Pittard W, Neuwald A . Natural mutagenesis of human genomes by endogenous retrotransposons. Cell. 2010; 141(7):1253-61. PMC: 2943760. DOI: 10.1016/j.cell.2010.05.020. View

14.

Beck C, Collier P, Macfarlane C, Malig M, Kidd J, Eichler E . LINE-1 retrotransposition activity in human genomes. Cell. 2010; 141(7):1159-70. PMC: 3013285. DOI: 10.1016/j.cell.2010.05.021. View

15.

Hancks D, Kazazian Jr H . Active human retrotransposons: variation and disease. Curr Opin Genet Dev. 2012; 22(3):191-203. PMC: 3376660. DOI: 10.1016/j.gde.2012.02.006. View

16.

Baillie J, Barnett M, Upton K, Gerhardt D, Richmond T, De Sapio F . Somatic retrotransposition alters the genetic landscape of the human brain. Nature. 2011; 479(7374):534-7. PMC: 3224101. DOI: 10.1038/nature10531. View

17.

Bourchis D, Bestor T . Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature. 2004; 431(7004):96-9. DOI: 10.1038/nature02886. View

18.

Kidd J, Graves T, Newman T, Fulton R, Hayden H, Malig M . A human genome structural variation sequencing resource reveals insights into mutational mechanisms. Cell. 2010; 143(5):837-47. PMC: 3026629. DOI: 10.1016/j.cell.2010.10.027. View

19.

Slovak M, Bedell V, Hsu Y, Estrine D, Nowak N, Delioukina M . Molecular karyotypes of Hodgkin and Reed-Sternberg cells at disease onset reveal distinct copy number alterations in chemosensitive versus refractory Hodgkin lymphoma. Clin Cancer Res. 2011; 17(10):3443-54. PMC: 3096736. DOI: 10.1158/1078-0432.CCR-10-1071. View

20.

Han J, Szak S, Boeke J . Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes. Nature. 2004; 429(6989):268-74. DOI: 10.1038/nature02536. View