1887

Abstract

Purpose. The tumour suppressor protein RB plays a decisive role in negative control of the cell cycle, inhibiting tumour development. The present analysis investigated the prevalence of the nucleotide polymorphism A153104G, which is located at intron 18 of the RB1 gene, and investigated the impact of the polymorphic variability in the exon 19 and its flanking intronic sequences on the severity of cervical disease in HPV16-positive Greek women.

Methodology. The nucleotide polymorphism A153104G was detected by PCR-RFLP assay, while the amplicons were further subjected to cloning and sequencing. Moreover, molecular evolutionary analysis was performed using the maximum-likelihood (ML) and empirical Bayesian (EB) methods in order to evaluate the selective pressure acting on exon 19 of the RB1 gene.

Results/Key findings. The A153104G nucleotide polymorphism was only detected in one control case. Moreover, sequence analysis of the amplicons revealed that the polymorphic variability in the RB1 gene increased with the severity of the cervical dysplasia. The link between the observed polymorphic variability and the progress of cervical disease was reflected in the molecular evolutionary analysis that was performed on the exon 19 of the RB1 gene, since negative selective pressure was acting upon exon 19 in the control and low-grade squamous intraepithelial lesion (LSIL) cervical samples, while positive selective pressure was acting upon exon 19 in the high-grade squamous intraepithelial lesion (HSIL) specimens.

Conclusions. The A153104G nucleotide polymorphism did not emerge as a potential biomarker for the development of precancerous lesions in the Greek patients, while the accumulation of sequence variations in RB1 gene might influence patients’ susceptibility towards the progression of cervical neoplasia.

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2018-10-10
2024-12-10
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References

  1. Zur Hausen H. Papillomavirus infections - a major cause of human cancers. Biochim Biophys Acta 1996; 1288:F55–F78[PubMed]
    [Google Scholar]
  2. Doorbar J, Quint W, Banks L, Bravo IG, Stoler M et al. The biology and life-cycle of human papillomaviruses. Vaccine 2012; 30:F55–F70 [View Article][PubMed]
    [Google Scholar]
  3. Tommasino M. The human papillomavirus family and its role in carcinogenesis. Semin Cancer Biol 2014; 26:13–21 [View Article][PubMed]
    [Google Scholar]
  4. Bernard HU, Burk RD, Chen Z, van Doorslaer K, Zur Hausen H et al. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology 2010; 401:70–79 [View Article][PubMed]
    [Google Scholar]
  5. Bernard HU, Calleja-Macias IE, Dunn ST. Genome variation of human papillomavirus types: phylogenetic and medical implications. Int J Cancer 2006; 118:1071–1076 [View Article][PubMed]
    [Google Scholar]
  6. Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci 2006; 110:525–541 [View Article][PubMed]
    [Google Scholar]
  7. GLOBOCAN The Global Cancer Observatory (GCO) is an interactive web-based platform presenting global cancer statistics to inform cancer control and research; 2012 http://globocan.iarc.fr [accessed 21 December 2017]
  8. Tsakogiannis D, Gartzonika C, Levidiotou-Stefanou S, Markoulatos P. Molecular approaches for HPV genotyping and HPV-DNA physical status. Expert Rev Mol Med 2017; 19:e1 [View Article][PubMed]
    [Google Scholar]
  9. de Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 2010; 11:1048–1056 [View Article][PubMed]
    [Google Scholar]
  10. Li N, Franceschi S, Howell-Jones R, Snijders PJ, Clifford GM. Human papillomavirus type distribution in 30,848 invasive cervical cancers worldwide: Variation by geographical region, histological type and year of publication. Int J Cancer 2011; 128:927–935 [View Article][PubMed]
    [Google Scholar]
  11. Ghittoni R, Accardi R, Chiocca S, Tommasino M. Role of human papillomaviruses in carcinogenesis. Ecancermedicalscience 2015; 9:526 [View Article][PubMed]
    [Google Scholar]
  12. Martinez-Zapien D, Ruiz FX, Poirson J, Mitschler A, Ramirez J et al. Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53. Nature 2016; 529:541–545 [View Article][PubMed]
    [Google Scholar]
  13. Olmedo-Nieva L, Muñoz-Bello JO, Contreras-Paredes A, Lizano M. The role of E6 spliced isoforms (E6*) in human papillomavirus-induced carcinogenesis. Viruses 2018; 10:E45 [View Article][PubMed]
    [Google Scholar]
  14. Aarthy M, Kumar D, Giri R, Singh SK. E7 oncoprotein of human papillomavirus: Structural dynamics and inhibitor screening study. Gene 2018; 658:159–177 [View Article][PubMed]
    [Google Scholar]
  15. Dick FA, Rubin SM. Molecular mechanisms underlying RB protein function. Nat Rev Mol Cell Biol 2013; 14:297–306 [View Article][PubMed]
    [Google Scholar]
  16. Dick FA, Goodrich DW, Sage J, Dyson NJ. Non-canonical functions of the RB protein in cancer. Nat Rev Cancer 2018; 18:442–451 [View Article][PubMed]
    [Google Scholar]
  17. Dyson NJ. RB1: a prototype tumor suppressor and an enigma. Genes Dev 2016; 30:1492–1502 [View Article][PubMed]
    [Google Scholar]
  18. Liban TJ, Medina EM, Tripathi S, Sengupta S, Henry RW et al. Conservation and divergence of C-terminal domain structure in the retinoblastoma protein family. Proc Natl Acad Sci USA 2017; 114:4942–4947 [View Article][PubMed]
    [Google Scholar]
  19. Narasimha AM, Kaulich M, Shapiro GS, Choi YJ, Sicinski P et al. Cyclin D activates the Rb tumor suppressor by mono-phosphorylation. Elife 2014; 3: [View Article][PubMed]
    [Google Scholar]
  20. Vélez-Cruz R, Johnson DG. The retinoblastoma (RB) tumor suppressor: pushing back against genome instability on multiple fronts. Int J Mol Sci 2017; 18:1776 [View Article][PubMed]
    [Google Scholar]
  21. Tsakogiannis D, Moschonas GD, Bella E, Kyriakopoulou Z, Amoutzias GD et al. Association of p16 (CDKN2A) polymorphisms with the development of HPV16-related precancerous lesions and cervical cancer in the Greek population. J Med Virol 2018; 90:965–971 [View Article][PubMed]
    [Google Scholar]
  22. Kolupaeva V, Janssens V. PP1 and PP2A phosphatases-cooperating partners in modulating retinoblastoma protein activation. FEBS J 2013; 280:627–643 [View Article][PubMed]
    [Google Scholar]
  23. Engel BE, Cress WD, Santiago-Cardona PG. The retinoblastoma protein: a master tumor suppressor acts as a link between cell cycle and cell adhesion. Cell Health Cytoskelet 2015; 7:1–10 [View Article][PubMed]
    [Google Scholar]
  24. Henley SA, Dick FA. The retinoblastoma family of proteins and their regulatory functions in the mammalian cell division cycle. Cell Div 2012; 7:10 [View Article][PubMed]
    [Google Scholar]
  25. Thakur N, Hussain S, Nasare V, das BC, Basir SF et al. Association analysis of p16 (CDKN2A) and RB1 polymorphisms with susceptibility to cervical cancer in Indian population. Mol Biol Rep 2012; 39:407–414 [View Article][PubMed]
    [Google Scholar]
  26. Casas I, Powell L, Klapper PE, Cleator GM. New method for the extraction of viral RNA and DNA from cerebrospinal fluid for use in the polymerase chain reaction assay. J Virol Methods 1995; 53:25–36 [View Article][PubMed]
    [Google Scholar]
  27. Tsakogiannis D, Diamantidou V, Toska E, Kyriakopoulou Z, Dimitriou TG et al. Multiplex PCR assay for the rapid identification of human papillomavirus genotypes 16, 18, 45, 35, 66, 33, 51, 58, and 31 in clinical samples. Arch Virol 2015; 160:207–214 [View Article][PubMed]
    [Google Scholar]
  28. Kadam-Pai P, Su X-Y, Miranda JJ, Soemantri A, Saha N et al. Ethnic variations of a retinoblastoma susceptibility gene (RB1) polymorphism in eight Asian populations. J Genet 2003; 82:33–37 [View Article]
    [Google Scholar]
  29. Tamura K, Dudley J, Nei M, Kumar S. MEGA4: molecular evolutionary genetics analysis (MEGA) software version 4.0. Mol Biol Evol 2007; 24:1596–1599 [View Article][PubMed]
    [Google Scholar]
  30. Edgar RC. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 2004; 32:1792–1797 [View Article][PubMed]
    [Google Scholar]
  31. Pond SL, Frost SD. Datamonkey: rapid detection of selective pressure on individual sites of codon alignments. Bioinformatics 2005; 21:2531–2533 [View Article][PubMed]
    [Google Scholar]
  32. Suzuki Y, Gojobori T. A method for detecting positive selection at single amino acid sites. Mol Biol Evol 1999; 16:1315–1328 [View Article][PubMed]
    [Google Scholar]
  33. Drummond AJ, Rambaut A. BEAST: Bayesian evolutionary analysis by sampling trees. BMC Evol Biol 2007; 7:214 [View Article][PubMed]
    [Google Scholar]
  34. McNair C, Xu K, Mandigo AC, Benelli M, Leiby B et al. Differential impact of RB status on E2F1 reprogramming in human cancer. J Clin Invest 2018; 128:341–358 [View Article][PubMed]
    [Google Scholar]
  35. Tomar S, Sethi R, Sundar G, Quah TC, Quah BL et al. Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling. PLoS One 2017; 12:e0178776 [View Article][PubMed]
    [Google Scholar]
  36. Yin M, Grivas P, Emamekhoo H, Mendiratta P, Ali S et al. ATM/RB1 mutations predict shorter overall survival in urothelial cancer. Oncotarget 2018; 9:16891–16898 [View Article][PubMed]
    [Google Scholar]
  37. Thangavel C, Boopathi E, Liu Y, Haber A, Ertel A et al. RB loss promotes prostate cancer metastasis. Cancer Res 2017; 77:982–995 [View Article][PubMed]
    [Google Scholar]
  38. Mol BM, Massink MP, van der Hout AH, Dommering CJ, Zaman JM et al. High resolution SNP array profiling identifies variability in retinoblastoma genome stability. Genes Chromosomes Cancer 2014; 53:1–14 [View Article][PubMed]
    [Google Scholar]
  39. Sagi M, Frenkel A, Eilat A, Weinberg N, Frenkel S et al. Genetic screening in patients with Retinoblastoma in Israel. Fam Cancer 2015; 14:471–480 [View Article][PubMed]
    [Google Scholar]
  40. Price EA, Price K, Kolkiewicz K, Hack S, Reddy MA et al. Spectrum of RB1 mutations identified in 403 retinoblastoma patients. J Med Genet 2014; 51:208–214 [View Article][PubMed]
    [Google Scholar]
  41. Knudsen ES, McClendon AK, Franco J, Ertel A, Fortina P et al. RB loss contributes to aggressive tumor phenotypes in MYC-driven triple negative breast cancer. Cell Cycle 2015; 14:109–122 [View Article][PubMed]
    [Google Scholar]
  42. Giacinti C, Giordano A. RB and cell cycle progression. Oncogene 2006; 25:5220–5227 [View Article][PubMed]
    [Google Scholar]
  43. Iwahori S, Umaña AC, Vandeusen HR, Kalejta RF. Human cytomegalovirus-encoded viral cyclin-dependent kinase (v-CDK) UL97 phosphorylates and inactivates the retinoblastoma protein-related p107 and p130 proteins. J Biol Chem 2017; 292:6583–6599 [View Article][PubMed]
    [Google Scholar]
  44. Kadam-Pai P, Su XY, Miranda JJ, Soemantri A, Saha N et al. Ethnic variations of a retinoblastoma susceptibility gene (RB1) polymorphism in eight Asian populations. J Genet 2003; 82:33–37 [View Article][PubMed]
    [Google Scholar]
  45. Schubert EL, Hansen MF. A previously unknown polymorphism located within the RB1 locus only present in Asian individuals. Hum Hered 1996; 46:118–120 [View Article][PubMed]
    [Google Scholar]
  46. Lesueur F, Song H, Ahmed S, Luccarini C, Jordan C et al. Single-nucleotide polymorphisms in the RB1 gene and association with breast cancer in the British population. Br J Cancer 2006; 94:1921–1926 [View Article][PubMed]
    [Google Scholar]
  47. Song H, Ramus SJ, Shadforth D, Quaye L, Kjaer SK et al. Common variants in RB1 gene and risk of invasive ovarian cancer. Cancer Res 2006; 66:10220–10226 [View Article][PubMed]
    [Google Scholar]
  48. Richter S, Vandezande K, Chen N, Zhang K, Sutherland J et al. Sensitive and efficient detection of RB1 gene mutations enhances care for families with retinoblastoma. Am J Hum Genet 2003; 72:253–269 [View Article][PubMed]
    [Google Scholar]
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