Frequent hypermethylation of RASSF1A tumour suppressor gene promoter and presence of Merkel cell polyomavirus in small cell lung cancer


      In small cell lung cancer (SCLC), hypermethylation of the tumour suppressor Ras association domain family 1A (RASSF1A) is frequent. It is associated with SV40 polyomaviral infection in other tumours. Merkel cell polyomavirus (MCPyV) infection has been reported in Merkel cell carcinoma (MCC), a neuroendocrine carcinoma with biological similarity to SCLC. In our study, we investigated polyomavirus infection (SV40 and MCPyV) and promoter hypermethylation of the tumour suppressors RASSF1A and p16 in 18 SCLCs (14 primaries and 4 regional lymph node metastases) and 18 blood control samples. MCPyV was found in 39% (7 of 18) of the tumour tissues but not observed in controls. SV40 was not observed in the tumour tissue. RASSF1A promoter hypermethylation (94%; 17 of 18) was more frequent compared to p16 methylation (56%, 10 of 18). We found no significant correlation between RASSF1A or p16 promoter hypermethylation and infection with the investigated polyoma viruses. Our results show a high frequency of hypermethylation of the RASSF1A promoter and occurrence of MCPyV infection in the tumour tissue of SCLC. These events may contribute to the pathogenesis of SCLC.


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        • Herbst R.S.
        • Heymach J.V.
        • Lippman S.M.
        Lung cancer.
        N Engl J Med. 2008; 359: 1367-1380
        • Owonikoko T.K.
        • Ramalingam S.
        Small cell lung cancer in elderly patients: a review.
        J Natl Compr Cancer Netw. 2008; 6: 333-344
        • Hosoe S.
        • Shigedo Y.
        • Ueno K.
        • et al.
        Detailed deletion mapping of the short arm of chromosome 3 in small cell and non-small cell carcinoma of the lung.
        Lung Cancer. 1994; 10: 297-305
        • Dammann R.
        • Takahashi T.
        • Pfeifer G.P.
        The CpG island of the novel tumor suppressor gene RASSF1A is intensely methylated in primary small cell lung carcinomas.
        Oncogene. 2001; 20: 3563-3567
        • Hachana M.
        • Trimeche M.
        • Ziadi S.
        • Amara K.
        • Korbi S.
        Evidence for a role of the Simian Virus 40 in human breast carcinomas.
        Breast Cancer Res Treat. 2008;
        • Liu L.
        • Zhang J.
        • Bates S.
        • et al.
        A methylation profile of in vitro immortalized human cell lines.
        Int J Oncol. 2005; 26: 275-285
        • Toyooka S.
        • Pass H.I.
        • Shivapurkar N.
        • et al.
        Aberrant methylation and simian virus 40 tag sequences in malignant mesothelioma.
        Cancer Res. 2001; 61: 5727-5730
        • Popp S.
        • Waltering S.
        • Herbst C.
        • Moll I.
        • Boukamp P.
        UV-B-type mutations and chromosomal imbalances indicate common pathways for the development of Merkel and skin squamous cell carcinomas.
        Int J Cancer. 2002; 99: 352-360
        • Van Gele M.
        • Boyle G.M.
        • Cook A.L.
        • et al.
        Gene-expression profiling reveals distinct expression patterns for classic versus variant Merkel cell phenotypes and new classifier genes to distinguish Merkel cell from small-cell lung carcinoma.
        Oncogene. 2004; 23: 2732-2742
        • Van Gele M.
        • Speleman F.
        • Vandesompele J.
        • Van Roy N.
        • Leonard J.H.
        Characteristic pattern of chromosomal gains and losses in Merkel cell carcinoma detected by comparative genomic hybridization.
        Cancer Res. 1998; 58: 1503-1508
        • Becker J.C.
        • Houben R.
        • Ugurel S.
        • Trefzer U.
        • Pfohler C.
        • Schrama D.
        MC polyomavirus is frequently present in Merkel cell carcinoma of European patients.
        J Invest Dermatol. 2008;
        • Feng H.
        • Shuda M.
        • Chang Y.
        • Moore P.S.
        Clonal integration of a polyomavirus in human Merkel cell carcinoma.
        Science. 2008; 319: 1096-1100
        • Garneski K.M.
        • Warcola A.H.
        • Feng Q.
        • Kiviat N.B.
        • Leonard J.H.
        • Nghiem P.
        Merkel cell polyomavirus is more frequently present in North American than Australian Merkel cell carcinoma tumors.
        J Invest Dermatol. 2008;
        • Kassem A.
        • Schopflin A.
        • Diaz C.
        • et al.
        Frequent detection of Merkel cell polyomavirus in human Merkel cell carcinomas and identification of a unique deletion in the VP1 gene.
        Cancer Res. 2008; 68: 5009-5013
      1. Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E. Histological Typing of lung and pleural tumours. 3rd ed. Berlin: World Health Organization, Springer; 1999.

        • Schagdarsurengin U.
        • Gimm O.
        • Hoang-Vu C.
        • Dralle H.
        • Pfeifer G.P.
        • Dammann R.
        Frequent epigenetic silencing of the CpG island promoter of RASSF1A in thyroid carcinoma.
        Cancer Res. 2002; 62: 3698-3701
        • Herman J.G.
        • Graff J.R.
        • Myohanen S.
        • Nelkin B.D.
        • Baylin S.B.
        Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands.
        Proc Natl Acad Sci USA. 1996; 93: 9821-9826
        • Agathanggelou A.
        • Cooper W.N.
        • Latif F.
        Role of the Ras-association domain family 1 tumor suppressor gene in human cancers.
        Cancer Res. 2005; 65: 3497-3508
        • Dammann R.
        • Schagdarsurengin U.
        • Seidel C.
        • et al.
        The tumor suppressor RASSF1A in human carcinogenesis: an update.
        Histol Histopathol. 2005; 20: 645-663
        • Richter A.M.
        • Pfeifer G.P.
        • Dammann R.H.
        The RASSF proteins in cancer; from epigenetic silencing to functional characterization.
        Biochim Biophys Acta. 2009;
        • Dammann R.
        • Li C.
        • Yoon J.H.
        • Chin P.L.
        • Bates S.
        • Pfeifer G.P.
        Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3.
        Nat Genet. 2000; 25: 315-319
        • Toyooka S.
        • Toyooka K.O.
        • Maruyama R.
        • et al.
        DNA methylation profiles of lung tumors.
        Mol Cancer Ther. 2001; 1: 61-67
        • Wang Y.
        • Yu Z.
        • Wang T.
        • Zhang J.
        • Hong L.
        • Chen L.
        Identification of epigenetic aberrant promoter methylation of RASSF1A in serum DNA and its clinicopathological significance in lung cancer.
        Lung cancer. 2007; 56: 289-294
        • Grote H.J.
        • Schmiemann V.
        • Geddert H.
        • et al.
        Methylation of RAS association domain family protein 1A as a biomarker of lung cancer.
        Cancer. 2006; 108: 129-134
        • Wang J.
        • Bhutani M.
        • Pathak A.K.
        • et al.
        Delta DNMT3B variants regulate DNA methylation in a promoter-specific manner.
        Cancer Res. 2007; 67: 10647-10652