Роль ретроэлементов в развитии наследственных опухолевых синдромов
https://doi.org/10.17650/2313-805X-2021-8-4-42-52
Аннотация
В развитии злокачественных новообразований большую роль играет геномная нестабильность, обусловленная активированными ретроэлементами. Происходит усиленная экспрессия онкогенов, которые содержат последовательности транспозонов в промоторах и интронах. При этом гены онкосупрессоров инактивируются, поскольку содержат горячие точки инсерционного мутагенеза. В то же время ретроэлементы содержат последовательности, чувствительные к негативному регуляторному влиянию онкосупрессоров. Поэтому их инактивация усиливает геномную нестабильность при канцерогенезе вследствие устранения сайленсинга ретроэлементов.
Цель статьи – описать механизмы влияния ретротранспозонов на развитие наследственных опухолевых синдромов, что позволит по-новому рассмотреть классические представления канцерогенеза.
Представленные данные позволяют пересмотреть двухударную гипотезу Кнудсона при наследственных опухолевых синдромах, поскольку герминативная инактивация 1 аллеля онкосупрессорного гена способствует развитию злокачественных опухолей из-за повышения активности транспозонов. Соматическая инактивация 2-го аллеля является не причиной, а следствием развившейся в неоплазме геномной нестабильности и может влиять на клональную эволюцию и прогрессирование канцерогенеза.
Ключевые слова
Об авторах
Р. Н. МустафинРоссия
Рустам Наилевич Мустафин
450008 Уфа, ул. Ленина, 3
Э. К. Хуснутдинова
Россия
450054 Уфа, пр-т Октября, 71
Список литературы
1. Hancks D.C., Kazazian H.H. Roles for retrotransposon insertions in human disease. Mob DNA 2016;7:9. DOI: 10.1186/s13100-016-0065-9.
2. Qian Y., Mancini-DiNardo D., Judkins T. et al. Identification of pathogenic retrotransposon insertions in cancer predisposition genes. Cancer Genet 2017;216–217:159–69. DOI: 10.1016/j.cancergen.2017.08.002.
3. Dabora S.L., Nieto A.A., Franz D. et al. Characterisation of six large deletions in TSC2 identified using long range PCR suggests diverse mechanisms including Alu mediated recombination. J Med Genet 2000;37(11):877–83. DOI: 10.1136/jmg.37.11.877.
4. Franke G., Bausch B., Hoffmann M.M. et al. Alu-Alu recombination underlies the vast majority of large VHL germline deletions: Molecular characterization and genotype-phenotype correlation in VHL patients. Hum Mutat 2009;30(5):776–86. DOI: 10.1002/humu.20948.
5. Hitchins M.P., Burn J. Alu in Lynch syndrome: a danger SINE. Cancer Prev Res (Phila) 2011;4(10):1527–30.
6. Wimmer K., Callens T., Wernstedt A. et al. The NF1 gene contains hotspots for L1 endonuclease-dependent de novo insertion. PLoS Genet 2011;7(11):e1002371. DOI: 10.1371/journal.pgen.1002371.
7. Crivelli L., Bubien V., Jones N. et al. Insertion of Alu elements at a PTEN hotspot in Cowden syndrome. Eur J Hum Genet 2017;25(9):1087–91. DOI: 10.38/ejhg.2017.81.
8. De Koning A.P., Gu W., Castoe T.A. et al. Repetitive elements may comprise over twothirds of the human genome. PLOS Genetics 2011;7(12):e1002384. DOI: 10.1371/journal.pgen.1002384.
9. Goerner-Potvin P., Bourque G. Computational tools to unmask transposable elements. Nat Rev Genet 2018;19:688–704. DOI: 10.1038/s41576-018-0050-x.
10. Kuhlen M., Borkhardt A. Cancer susceptibility syndromes in children in the area of broad clinical use of massive parallel sequencing. Eur J Pediatr 2015;174(8):987–97.
11. Имянитов Е.Н., Хансон К.П. Молекулярная генетика в клинической онкологии. Сибирский онкологический журнал 2004;2–3:40–7.
12. Wang T., Zeng J., Lowe C.B. et al. Speciesspecific endogenous retroviruses shape the transcriptional network of the human tumor suppressor protein p53. Proc Natl Acad Sci 2007;104(47):18613–8. DOI: 10.1073/pnas.0703637104.
13. Cherkasova E., Malinzak E., Rao S. et al. Inactivation of the von Hippel–Lindau tumor suppressor leads to selective expression of a human endogenous retrovirus in kidney cancer. Oncogene 2011;30(47):4697–706. DOI: 10.1038/onc.2011.179.
14. Montoya-Durango D.E., Ramos K.S. Retinoblastoma famiy of proteins and chromatin epigenetics: a repetitive story in a few LINEs. Biomol Concepts 2011;2(4):233–45. DOI: 10.1515/bmc.2011.027.
15. Mita P., Sun X., Fenyo D. et al. BRCA1 and S phase DNA repair pathways restrict LINE-1 retroptransposition in human cells. Nat Struct Mol Biol 2020;27(2):179–91. DOI: 10.1038/s41594-020-0374-z.
16. Tiwari B., Jones A.E., Caillet C.J. et al. P53 directly repress human LINE1 transposons. Genes Dev 2020;34(21–22):1439–51. DOI: 10.1101/gad.343186.120.
17. Lamprecht B., Walter K., Kreher S. et al. Derepression of an endogenous long terminal repeat activates the CSF1R protooncogene in human lymphoma. Nat Med. 2010;16(5):571–9. DOI: 10.1038/nm.2129.
18. Hur K., Cejas P., Feliu J. et al. Hypomethylation of long interspersed nuclear element-1 (LINE-1) leads to activation of proto-oncogenes in human colorectal cancer metastasis. Gut 2014;63(4):635–46. DOI: 10.1136/gutjnl-2012-304219.
19. Babaian A., Romanish M.T., Gagnier L. et al. Onco-exaptation of an endogenous retroviral LTR drives IRF5 expression in Hodgkin lymphoma. Oncogene 2016;35(19):2542–6. DOI: 10.1038/onc.2015.308.
20. Lock F.E., Rebollo R., Miceli-Royer K. et al. Distinct isoform of FABP7 revealed by screening for retroelement-activated genes in diffuse large B-cell lymphoma. Proc Natl Acad Sci 2014;111(34):E3534–43. DOI:10.1073/pnas.1405507111.
21. Wiesner T., Lee W., Obenauf A.C. et al. Alternative transcription initiation leads to expression of a novel ALK isoform in cancer. Nature 2015;526(7573):453–7. DOI: 10.1038/nature15258.
22. Scarfò I., Pellegrino E., Mereu E. et al. Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts. Blood 2016;127(2):221–32. DOI: 10.1182/blood-2014-12-614503.
23. Cervantes-Ayalc A., Esparza-Garrido R.R., Velazquez-Floes M.A. Long Interspersed Nuclear Elements 1 (LINE1): The chimeric transcript L1-MET and its involvement in cancer. Cancer Genet 2020;241:1–11. DOI: 10.1016/j.cancergen.2019.11.004.
24. Thunders M., Delahunt B. Gene of the month: DICER1: ruler and controller. J Clin Pathol 2021;74(2):69–72. DOI: 10.1136/jclinpath-2020-207203.
25. Maki-Nevala S., Valo S., Ristimaki A. et al. DNA methylation changes and somatic mutations as tumorigenic events in Lynch syndrome-associated adenomas retaining mismatch repair protein expression. EBioMedicine 2019;39:280–91. DOI: 10.1016/j.ebiom.2018.12.018.
26. Rodriguez-Martin B., Alvarez E.G., Baez-Ortega A. et al. Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition. Nat Genet 2020;52(3):306–19. DOI: 10.1038/s41588-019-0562-0.
27. Cortes-Ciriano I., Lee J.J., Xi R. et al. Comprehensive analysis of chromothripsis in 2658 human cancer using whole-genome sequencing. Nat Genet 2020;52(3):331–41. DOI: 10.1038/s41588-019-0576-7.
28. Nazaryan-Petersen L., Bertelsen B., Bak M. et al. Germline chromothripsis driven by L1-mediated retrotransposition and Alu/Alu homologous recombination. Hum Mutat 2016;37(4):385–95. DOI: 10.1002/humu.22953.
29. Erwin J.A., Paquola A.C.M., Singer T. et al. L1-Associated Genomic Regions are Deleted in Somatic Cells of the Healthy Human Brain. Nat Neurosci 2016;19(12):1583–91. DOI: 10.1038/nn.4388.
30. Chen J.M., Cooper D.N. A mechanistic link between L1 retrotransposition and chromothripsis. Hum Mutat 2016;37(4):329. DOI: 10.1002/humu.22870.
31. Symer D.E., Connelly C., Szak S.T. et al. Human L1 retrotransposition is associated with genetic instability in vivo. Cell 2002;110(3):327–38. DOI: 10.1016/s0092-8674(02)00839-5.
32. Vogt J., Bengesser K., Claes K.B.M. et al. SVA retrotransposon insertion-associated deletion represents a novel mutational mechanism underlying large genomic copy number changes with non-recurrent breakpoints. Genome Biol 2014;15:R80.
33. Poot M. Genes, proteins, and biological pathways preventing chromothripsis. Methods Mol Biol 2018;1769:231–51. DOI: 10.1007/978-1-4939-7780-2_15.
34. Anwar S.L., Wulaningsih W., Lehmann U. Transposable elements in human cancer: causes and consequences of deregulation. Int J Mol Sci 2017;18(5):pii: E974. DOI: 10.3390/ijms18050974.
35. Bermejo A.V., Ragonnaud E., Daradoumis J. et al. Cancer associated endogenous retroviruses: ideal immune target for adenovirus-based immunotherapy. Int J Mol Sci 2020;21(14):4843. DOI: 10.3390/ijms21144843.
36. Harris C.R., Dewan A., Zupnick A. et al. P53 responsive elements in human retrotransposons. Oncogene 2009;28(44):3857–65. DOI: 10.1038/onc.2009.246.
37. Coufal N.G., Garcia-Perez J.L., Peng G.E. et al. Ataxia telangiectasia mutated (ATM) modulates long interspersed element-1 (L1) retrotransposition in human neural stem cells. Proc Natl Acad Sci USA 2011;108(51):20382–7. DOI: 10.1073/pnas.1100273108.
38. Guendel I., Meltzer B.W., Baer A. et al. BRCA1 functions as a novel transcriptional cofactor in HIV-1 infection. Virol J 2015;12:40. DOI: 10.1186/s12985-015-0266-8.
39. Coyle-Rink J., Sweet T., Abraham S. et al. Interaction between TGFbeta signaling proteins and C/EBP controls basal and Tatmediated transcription of HIV-1 LTR in astrocytes. Virology 2002;299(2):240–7. DOI: 10.1006/viro.2002.1439.
40. Miret N., Zappia C.D., Altamirano G. et al. AhR ligands reactivate LINE-1 retrotransposon in triple-negative breast cancer cells MDA-MB-231 and non-tumorigenic mammary epithelial cells NMuMG. Biochem Pharmacol 2020;175:113904. DOI: 10.1016/j.bcp.2020.113904.
41. Sotero-Caio C.G., Platt R.N., Suh A., Ray D.A. Evolution and diversity of transposable elements in vertebrate genomes. Genome Biol Evol 2017;9(1):161–77. DOI: 10.1093/gbe/evw264.
42. Solassol J., Larrieux M., Leclerc J. et al. Alu element insertion in the MLH1 exon 6 coding sequence as a mutation predisposing to Lynch syndrome. Hum Mutat 2019;40(6):716–20. DOI: 10.1002/humu.23725.
43. Machado P.M., Brandao R.D., Cavaco B.M. et al. Screening for a BRCA2 rearrangement in high-risk breast/ovarian cancer families: evidence for a founder effect and analysis of the associated phenotypes. J Clin Oncol 2007;25(15):2027–34. DOI: 10.1200/JCO.2006.06.9443.
44. Peixoto A., Santos C., Pinto P. The role of targeted BRCA1/BRCA2 mutation analysis in hereditary breast/ovarian cancer families of Portuguese ancestry. Clin Genet 2015;88(1):41–8. DOI: 10.1111/cge.12441.
45. Yoshiji S., Iwasaki Y., Iwasaki K. et al. Alumediated MEN1 gene deletion and loss of heterozygosity in patient with multiple endocrine neoplasia type1 2020;4(8):bvaa051. DOI: 10.1210/jendso/bvaa051.
46. Fujii K., Ishikawa S., Uchikawa H. et al. High-density oligonucleotide array with subkilobase resolution reveals breakpoint information of submicroscopic deletions in nevoid basal cell carcinoma syndrome. Hum Genet 2007;122(5):459–66. DOI: 10.1007/s00439-007-0419-y.
47. Borun P., De Rosa M., Nedoszytko B. et al. Specific Alu elements involved in a significant percentage of copy number variations of the STK11 gene in patients with Peutz–Jeghers syndrome. Fam Cancer 2015;14(3):455–61. DOI: 10.1007/s10689-015-9800-5.
48. Rodriguez-Martin C., Cidre F., FernandezTeijeiro A. et al. Familial retinoblastoma due to intronic LINE-1 insertion causes aberrant and noncanonical mRNA splicing of the RB1 gene. J Hum Genet 2016;61(5):463–6. DOI: 10.1038/jhg.2015.173.
49. Ramos K.S., Montoya-Durango D.E., Teneng I. et al. Epigenetic control of embryonic renal cell differentiation by L1 retrotransposon. Birth Defects Res. A Clin Mol Teratol 2011;91(8):693–702. DOI: 10.1002/bdra.20786.
50. Garen A. From a retrovirus infection of mice to a long noncoding RNA that induces proto-oncogene transcription and oncogenesis via an epigenetic transcription switch. Signal Transduct. Target Ther 2016;1:16007. DOI: 10.1038/sigtrans.2016.7.
51. Jang H.S., Shah N.M., Du A.Y. et al. Transposable elements drive widespread expression of oncogenes in human cancer. Nat Genet 2019;51(4):611–7. DOI: 10.1038/s41588-019-0373-3.
52. Chen T., Meng Z., Gan Y. et al. The viral oncogene Np9 acts as a critical molecular switch for co-activating beta-catenin, ERK, Akt and Notch1 and promoting the growth of human leukemia stem/progenitor cells. Leukemia 2013;27(7):1469–78.
53. Fairbanks D.J., Fairbanks A.D., Ogden T.H. et al. NANOGP8: evolution of a human-specific retro-oncogene. G3 (Bethesda) 2012;2(11):1447–57. DOI: 10.1534/g3.112.004366.
Рецензия
Для цитирования:
Мустафин Р.Н., Хуснутдинова Э.К. Роль ретроэлементов в развитии наследственных опухолевых синдромов. Успехи молекулярной онкологии. 2021;8(4):42-52. https://doi.org/10.17650/2313-805X-2021-8-4-42-52
For citation:
Mustafin R.N., Khusnutdinova E.K. The role of retroelements in the development of hereditary tumor syndromes. Advances in Molecular Oncology. 2021;8(4):42-52. (In Russ.) https://doi.org/10.17650/2313-805X-2021-8-4-42-52