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Open Access 01-12-2015 | Research

Expression of pRb and p16INK4 in human thymic epithelial tumors in relation to the presence of human polyomavirus 7

Authors: Marlies Keijzers, Dorit Rensspiess, Sreedhar Pujari, Myrurgia A. Abdul-Hamid, Monique Hochstenbag, Anne-Marie Dingemans, Anna Kordelia Kurz, Anke Haugg, Jos. G. Maessen, Marc H. De Baets, Axel zur Hausen

Published in: Diagnostic Pathology | Issue 1/2015

Abstract

Background

We have recently reported the presence of the Human polyomavirus 7 (HPyV7) in human thymic epithelial tumors as assessed by diverse molecular techniques. Here we report on the co-expression of p16, retinoblastoma protein (pRb) and phosphorylated retinoblastoma protein (phospho-Rb) in human thymic epithelial tumors in relation to HPyV7.

Methods

PRB, phospho-RB and p16 expression was assessed by immuno-histochemistry in 37 thymomas and 2 thymic carcinomas. 17 thymomas (46 %) and 1 thymic carcinoma (50 %) were recently tested positive for HPyV7. In addition, 20 follicular hyperplasias were tested.

Results

Expression of pRb was observed in 35 thymomas (94.6 %), in 16 thymomas (43.2 %) the expression was strong. Phospho-Rb was observed in 31 thymomas (83.8 %). 19 thymomas (51.4 %) showed immunoreactivity for p16 of which 8 thymomas revealed very strong p16 expression. No p16 expression was detected in thymic carcinomas. In addition, no significant correlation between the presence of HPyV7 and pRb-, phospho-Rb- and p16-expression could be established. No correlation between pRb, phospho-Rb, p16 and WHO staging, Masaoka-Koga staging or the presence of MG was found. All 20 follicular hyperplasias showed expression of pRb and less expression of phospho-Rb.

Conclusions

Although polyomaviruses have been shown to interact with cell cycle proteins no correlation between the presence of HPyV7 and the expression of pRb, phospho-Rb and p16 in human thymic epithelial tumors was observed. In as much HPyV7 contributes to human thymomagenesis remains to be established. Our data indicate pRb, phospho-Rb and p16 expression are rather unlikely to be involved in HPyV7 related thymomagenesis.

Cavalcante P, Barberis M, Cannone M, Baggi F, Antozzi C, Maggi L, et al. Detection of poliovirus-infected macrophages in thymus of patients with myasthenia gravis. Neurology. 2010;74(14):1118–26. doi:10.1212/WNL.0b013e3181d7d884.CrossRefPubMed

McGuire LJ, Huang DP, Teoh R, Arnold M, Wong K, Lee JC. Epstein-Barr virus genome in thymoma and thymic lymphoid hyperplasia. Am J Pathol. 1988;131(3):385–90.PubMedCentralPubMed

Inghirami G, Chilosi M, Knowles DM. Western thymomas lack Epstein-Barr virus by Southern blotting analysis and by polymerase chain reaction. Am J Pathol. 1990;136(6):1429–36.PubMedCentralPubMed

Sanjuan N, Porras A, Otero J, Perazzo S. Expression of major capsid protein VP-1 in the absence of viral particles in thymomas induced by murine polyomavirus. J Virol. 2001;75(6):2891–9. doi:10.1128/JVI.75.6.2891-2899.2001.PubMedCentralCrossRefPubMed

Wirth JJ, Fluck MM. Immunological elimination of infected cells as the candidate mechanism for tumor protection in polyomavirus-infected mice. J Virol. 1991;65(12):6985–8.PubMedCentralPubMed

Rennspiess D, Pujari S, Keijzers M, Abdul-Hamid MA, Hochstenbag M, Dingemans A et al. Detection of Human Polyomavirus 7 in human thymic epithelial tumors. J Thorac Oncol. 2014. doi:10.1097/JTO.0000000000000390

Schowalter RM, Pastrana DV, Pumphrey KA, Moyer AL, Buck CB. Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin. Cell Host Microbe. 2010;7(6):509–15. doi:10.1016/j.chom.2010.05.006.PubMedCentralCrossRefPubMed

Van Ghelue M, Khan MT, Ehlers B, Moens U. Genome analysis of the new human polyomaviruses. Rev Med Virol. 2012;22(6):354–77. doi:10.1002/rmv.1711.CrossRefPubMed

Siebrasse EA, Reyes A, Lim ES, Zhao G, Mkakosya RS, Manary MJ, et al. Identification of MW polyomavirus, a novel polyomavirus in human stool. J Virol. 2012;86(19):10321–6. doi:10.1128/JVI.01210-12.PubMedCentralCrossRefPubMed

10.

DeCaprio JA, Garcea RL. A cornucopia of human polyomaviruses. Nat Rev Microbiol. 2013;11(4):264–76. doi:10.1038/nrmicro2992.PubMedCentralCrossRefPubMed

11.

Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319(5866):1096–100. doi:10.1126/science.1152586.PubMedCentralCrossRefPubMed

12.

Foulongne V, Kluger N, Dereure O, Brieu N, Guillot B, Segondy M. Merkel cell polyomavirus and Merkel cell carcinoma, France. Emerg Infect Dis. 2008;14(9):1491–3. doi:10.3201/eid1409.080651.PubMedCentralCrossRefPubMed

13.

Shuda M, Feng H, Kwun HJ, Rosen ST, Gjoerup O, Moore PS, et al. T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. Proc Natl Acad Sci U S A. 2008;105(42):16272–7. doi:10.1073/pnas.0806526105.PubMedCentralCrossRefPubMed

14.

Houben R, Adam C, Baeurle A, Hesbacher S, Grimm J, Angermeyer S, et al. An intact retinoblastoma protein-binding site in Merkel cell polyomavirus large T antigen is required for promoting growth of Merkel cell carcinoma cells. Int J Cancer. 2012;130(4):847–56. doi:10.1002/ijc.26076.CrossRefPubMed

15.

Pipas JM, Levine AJ. Role of T antigen interactions with p53 in tumorigenesis. Semin Cancer Biol. 2001;11(1):23–30. doi:10.1006/scbi.2000.0343.CrossRefPubMed

16.

Harms PW, Patel RM, Verhaegen ME, Giordano TJ, Nash KT, Johnson CN, et al. Distinct gene expression profiles of viral- and nonviral-associated merkel cell carcinoma revealed by transcriptome analysis. J Invest Dermatol. 2013;133(4):936–45. doi:10.1038/jid.2012.445.PubMedCentralCrossRefPubMed

17.

DeCaprio JA. How the Rb tumor suppressor structure and function was revealed by the study of Adenovirus and SV40. Virology. 2009;384(2):274–84. doi:10.1016/j.virol.2008.12.010.CrossRefPubMed

18.

Rozenblatt-Rosen O, Deo RC, Padi M, Adelmant G, Calderwood MA, Rolland T, et al. Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature. 2012;487(7408):491–5. doi:10.1038/nature11288.PubMedCentralCrossRefPubMed

19.

Berrios C, Jung J, Primi B, Wang M, Pedamallu C, Duke F, et al. Malawi polyomavirus is a prevalent human virus that interacts with known tumor suppressors. J Virol. 2015;89(1):857–62. doi:10.1128/JVI.02328-14.PubMedCentralCrossRefPubMed

20.

Felsani A, Mileo AM, Paggi MG. Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins. Oncogene. 2006;25(38):5277–85. doi:10.1038/sj.onc.1209621.CrossRefPubMed

21.

Cufi P, Soussan P, Truffault F, Fetouchi R, Robinet M, Fadel E, et al. Thymoma-associated myasthenia gravis: On the search for a pathogen signature. J Autoimmun. 2014;52:29–35. doi:10.1016/j.jaut.2013.12.018.CrossRefPubMed

22.

Dehn D, Torkko KC, Shroyer KR. Human papillomavirus testing and molecular markers of cervical dysplasia and carcinoma. Cancer. 2007;111(1):1–14. doi:10.1002/cncr.22425.CrossRefPubMed

23.

Hirabayashi H, Fujii Y, Sakaguchi M, Tanaka H, Yoon HE, Komoto Y, et al. p16INK4, pRB, p53 and cyclin D1 expression and hypermethylation of CDKN2 gene in thymoma and thymic carcinoma. Int J Cancer. 1997;73(5):639–44.CrossRefPubMed

24.

Omatsu M, Kunimura T, Mikogami T, Shiokawa A, Masunaga A, Nagai T, et al. Cyclin-dependent kinase inhibitors, p16 and p27, demonstrate different expression patterns in thymoma and thymic carcinoma. Gen Thorac Cardiovasc Surg. 2014;62(11):678–84. doi:10.1007/s11748-014-0437-3.CrossRefPubMed

25.

Rosai J. Histological typing of tumour of the thymus (ed 2nd). Berlin and Heidelberg: Springer-Verslag; 1999.CrossRef

26.

Masaoka A. Staging system of thymoma. J Thorac Oncol. 2010;5(10 Suppl 4):S304–12. doi:10.1097/JTO.0b013e3181f20c05.CrossRefPubMed

27.

Redman R, Rufforny I, Liu C, Wilkinson EJ, Massoll NA. The utility of p16(Ink4a) in discriminating between cervical intraepithelial neoplasia 1 and nonneoplastic equivocal lesions of the cervix. Arch Pathol Lab Med. 2008;132(5):795–9. doi:10.1043/1543-2165(2008)132[795:TUOPID]2.0.CO;2.PubMed

28.

Klingenberg B, Hafkamp HC, Haesevoets A, Manni JJ, Slootweg PJ, Weissenborn SJ, et al. p16 INK4A overexpression is frequently detected in tumour-free tonsil tissue without association with HPV. Histopathology. 2010;56(7):957–67. doi:10.1111/j.1365-2559.2010.03576.x.CrossRefPubMed

29.

Detterbeck FC, Nicholson AG, Kondo K, Van Schil P, Moran C. The Masaoka-Koga stage classification for thymic malignancies: clarification and definition of terms. J Thorac Oncol. 2011;6(7 Suppl 3):S1710–6. doi:10.1097/JTO.0b013e31821e8cff.CrossRefPubMed

Title: Expression of pRb and p16INK4 in human thymic epithelial tumors in relation to the presence of human polyomavirus 7
Authors: Marlies Keijzers
Dorit Rensspiess
Sreedhar Pujari
Myrurgia A. Abdul-Hamid
Monique Hochstenbag
Anne-Marie Dingemans
Anna Kordelia Kurz
Anke Haugg
Jos. G. Maessen
Marc H. De Baets
Axel zur Hausen
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Diagnostic Pathology / Issue 1/2015
Electronic ISSN: 1746-1596
DOI: https://doi.org/10.1186/s13000-015-0418-6

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Springer Medicine

Expression of pRb and p16INK4 in human thymic epithelial tumors in relation to the presence of human polyomavirus 7

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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