Preview

Advances in Molecular Oncology

Advanced search

The role of retroelements in the development of hereditary tumor syndromes

https://doi.org/10.17650/2313-805X-2021-8-4-42-52

Abstract

Genomic instability caused by activated retroelements plays an important role in the development of malignant neoplasms. Activated retroelements cause enhanced expression of oncogenes containing transposon sequences in their promoters and introns. Oncosuppressor genes contain hot spots of insertional mutagenesis, therefore retroelements cause their inactivation. As a result, genomic instability increases during the development of tumors, since oncosuppressors normally silence retrotransposons. Accordingly, inactivation of the oncosuppressor causes increased expression of retroelements.

The study objective is to describe the role of retrotransposons on the development of hereditary tumor syndromes, which will allow a new look at the classical concepts of carcinogenesis. The data we have described allow us to consider in a new way the Knudson’s two-hit hypothesis in hereditary tumor syndromes, since the germinal inactivation of 1 allele of the oncosuppressor gene promotes the development of malignant tumors due to an increase in the activity of transposons. The consequence of the developed instability in the tumor is the inactivation of the second allele of the oncosuppressor gene, which contributes to clonal evolution and the progression of carcinogenesis.

About the Authors

R. N. Mustafin
Bashkir State Medical University
Russian Federation

Rustam Nailevich Mustafin

3 Lenin St., Ufa 450008



E. K. Khusnutdinova
Institute of Biochemistry and Genetics of the Ufa Federal Research Center of Russian Academy of Sciences
Russian Federation

71 Prospekt Oktyabrya, Ufa 450054



References

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. Imyanitov E.N., Hanson K.P. Molecular genetics in clinical oncology. Sibirskij onkologicheskij zhurnal = Siberian Journal of Oncology 2004;2–3: 40–7. (In Russ.).

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.


Review

For citations:


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

Views: 352


Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.


ISSN 2313-805X (Print)
ISSN 2413-3787 (Online)