Abstract
Testicular germ cell tumours (TGCTs) are histologically heterogeneous neoplasms with variable malignant potential. Previously, we demonstrated frequent 3p allele loss in TGCTs, and recently we and others have shown that the 3p21.3 RASSF1A tumour suppressor gene (TSG) is frequently inactivated by promoter hypermethylation in a wide range of cancers including lung, breast, kidney and neuroblastoma. In order to investigate the role of epigenetic events in the pathogenesis of TGCTs, we analysed the promoter methylation status of RASSF1A and nine other genes that may be epigenetically inactivated in cancer (p16INK4A, APC, MGMT, GSTP1, DAPK, CDH1, CDH13, RARĪ² and FHIT) in 24 primary TGCTs (28 histologically distinct components). RASSF1A methylation was detected in four of 10 (40%) seminomas and 15 of 18 (83%) nonseminoma TGCT (NSTGCT) components (P=0.0346). None of the other nine candidate genes were methylated in seminomas, but MGMT (44%), APC (29%) and FHIT (29%) were frequently methylated in NSTGCTs. Furthermore, in two mixed germ cell tumours, the NSTGCT component for one demonstrated RASSF1A, APC and CDH13 promoter methylation, but the seminoma component was unmethylated for all genes analysed. In the second mixed germ cell tumour, the NSTGCT component was methylated for RASSF1A and MGMT, while the seminoma component was methylated only for RASSF1A. In all, 61% NSTGCT components but no seminoma samples demonstrated promoter methylation at two or more genes (P=0.0016). These findings are consistent with a multistep model for TGCT pathogenesis in which RASSF1A methylation occurs early in tumorigenesis and additional epigenetic events characterize progression from seminoma to NSTGCTs.
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References
Agathanggelou A, Honorio S, Macartney DP, Martinez A, Dallol A, Rader J, Fullwood P, Chauhan A, Walker R, Shaw JA, Hosoe S, Lerman MI, Minna JD, Maher ER and Latif F . (2001). Oncogene, 20, 1509ā1518.
Al-Jehani RM, Povey S, Delhanty JD and Parrington JM . (1995). Genes Chromosomes Cancer, 13, 249ā256.
Astuti D, Agathanggelou A, Honorio S, Dallol A, Martinsson T, Kogner P, Cummins C, Neumann HP, Voutilainen R, Dahia P, Eng C, Maher ER and Latif F . (2001). Oncogene, 20, 7573ā7577.
Burbee DG, Forgacs E, Zochbauer-Muller S, Shivakumar L, Fong K, Gao B, Randle D, Kondo M, Virmani A, Bader S, Sekido Y, Latif F, Milchgrub S, Toyooka S, Gazdar AF, Lerman MI, Zabarovsky E, White M and Minna JD . (2001). J. Natl. Cancer Inst., 93, 691ā699.
Byun DS, Lee MG, Chae KS, Ryu BG and Chi SG . (2001). Cancer Res., 61, 7034ā7038.
Chaganti RSK and Houldsworth L . (2000). Cancer Res., 60, 1475ā1482.
Chaubert P, Guillou L, Kurt AM, Bertholet MM, Metthez G, Leisinger HJ, Bosman F and Shaw P . (1997). Am. J. Pathol., 151, 859ā865.
Dammann R, Li C, Yoon JH, Chin PL, Bates S and Pfeifer GP . (2000). Nat. Genet., 25, 315ā319.
Dammann R, Takahashi T and Pfeifer GP . (2001). Oncogene, 20, 3563ā3567.
Dreijerink K, Braga E, Kuzmin I, Geil L, Duh FM, Angeloni D, Zbar B, Lerman MI, Stanbridge EJ, Minna JD, Protopopov A, Li J, Kashuba V, Klein G and Zabarovsky ER . (2001). Proc. Natl. Acad. Sci. USA, 98, 7504ā7509.
Esteller M, Corn PG, Baylin SB and Herman JG . (2001). Cancer Res., 61, 3225ā3229.
Esteller M, Corn PG, Urena JM, Gabrielson E, Baylin SB and Herman JG . (1998). Cancer Res., 58, 4515ā4518.
Esteller M, Hamilton SR, Burger PC, Baylin SB and Herman JG . (1999). Cancer Res., 59, 793ā797.
Faulkner SW, Leigh DA, Oosterhuis JW, Roelofs H, Looijenga LH and Friedlander ML . (2000). Br J Cancer, 83, 729ā736.
Fearon ER and Vogelstein BA . (1990). Cell, 61, 759ā767.
Foster K, Osborne RJ, Huddart RA, Affara NA, Ferguson-Smith MA and Maher ER . (1995). Eur J Cancer, 31A, 2392ā2395.
Graff JR, Herman JG, Myohanen S, Baylin SB and Vertino PM . (1997). J. Biol. Chem., 272, 22322ā22329.
Herman JG, Graff JR, Myohanen S, Nelkin BD and Baylin SB . (1996). Proc. Natl. Acad. Sci. USA, 93, 9821ā9826.
Katzenellenbogen RA, Baylin SB and Herman JG . (1999). Blood, 93, 4347ā4353.
Kraggerud SM, Aman P, Holm R, Stenwig AE, Fossa SD, Nesland JM and Lothe RA . (2002). Cancer Res., 62, 512ā517.
Lee MG, Kim HY, Byun DS, Lee SJ, Lee CH, Kim JI, Chang SG and Chi SG . (2001). Cancer Res., 61, 6688ā6692.
Lerman MI and Minna JD . (2000). Cancer Res., 60, 6116ā6133.
Lind GE, Smith-Soerensen B, Skotheim RI, Fossaa SD, Fodstad O, Stenwig AE, Jakobsen KS and Lothe RA . (2002). Proceedings of the American Association for Cancer Research, 93rd Annual Meeting, Vol. 43, p. 1120.
Lo KW, Kwong J, Hui AB, Chan SY, To KF, Chan AS, Chow LS, Teo PM, Johnson PJ and Huang DP . (2001). Cancer Res., 61, 3877ā3881.
Looijenga LH, Abraham M, Gillis AJ, Saunders GF and Oosterhuis JW . (1994). Genes Chromosomes Cancer, 9, 153ā160.
Looijenga LH, Gillis AJ, van Gurp RJ, Verkerk AJ and Oosterhuis JW . (1997). Am. J. Pathol., 151, 581ā590.
Looijenga LHJ and Oosterhuis JW . (1999). Rev. Reprod., 4, 90ā100.
Lothe RA, Peltomaki P, Tommerup N, Fossa SD, Stenwig AE, Borresen AL and Nesland JM . (1995). Lab Invest., 73, 606ā614.
Maruyama R, Toyooka S, Toyooka KO, Virmani AK, Zochbauer-Muller S, Farinas AJ, Minna JD, McConnell J, Frenkel EP and Gazdar AF . (2002). Clin. Cancer Res., 8, 514ā519.
Mathew S, Murty VV, Bosl GJ and Chaganti RS . (1994). Cancer Res., 54, 6265ā6269.
Morrissey C, Martinez A, Zatyka M, Agathanggelou A, Honorio S, Astuti D, Morgan NV, Moch H, Richards FM, Kishida T, Yao M, Schraml P, Latif F and Maher ER . (2001). Cancer Res., 61, 7277ā7281.
Mostert MC, Verkerk AJ, van de Pol M, Heighway J, Marynen P, Rosenberg C, van Kessel AG, van Echten J, de Jong B, Oosterhuis JW and Looijenga LH . (1998). Oncogene, 16, 2617ā2627.
Murty VV, Reuter VE, Bosl GJ and Chaganti RS . (1996). Oncogene, 12, 2719ā2723.
Peltomaki P . (1991). Biochim. Biophys. Acta, 1096, 187ā196.
Rothe M, Albers P and Wernert N . (1999). J. Pathol., 188, 389ā394.
Smiraglia DJ, Szymanska J, Kraggerud SM, Lothe RA, Peltomaki P and Plass C . (2002). Oncogene, 21, 3909ā3916.
Suijkerbuijk RF, Sinke RJ, Weghuis DE, Roque L, Forus A, Stellink F, Siepman A, van de Kaa C, Soares J and Geurts van Kessel A . (1994). Cancer Genet Cytogenet., 78, 145ā152.
Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB and Issa JP . (1999a). Proc. Natl. Acad. Sci. USA, 96, 8681ā8686.
Toyota M, Ahuja N, Suzuki H, Itoh F, Ohe-Toyota M, Imai K, Baylin SB and Issa JP . (1999b). Cancer Res., 59, 5438ā5442.
Toyooka KO, Toyooka S, Virmani AK, Sathyanarayana UG, Euhus DM, Gilcrease M, Minna JD and Gazdar AF . (2001). Cancer Res., 61, 4556ā4560.
Tsuchiya T, Tamura G, Sato K, Endoh Y, Sakata K, Jin Z, Motoyama T, Usuba O, Kimura W, Nishizuka S, Wilson KT, James SP, Yin J, Fleisher AS, Zou T, Silverberg SG, Kong D and Meltzer SJ . (2000). Oncogene, 19, 3642ā3646.
Virmani AK, Rathi A, Zochbauer-Muller S, Sacchi N, Fukuyama Y, Bryant D, Maitra A, Heda S, Fong KM, Thunnissen F, Minna JD and Gazdar AF . (2000). J. Natl. Cancer Inst., 92, 1303ā1307.
Zochbauer-Muller S, Fong KM, Maitra A, Lam S, Geradts J, Ashfaq R, Virmani AK, Milchgrub S, Gazdar AF and Minna JD . (2001). Cancer Res., 61, 3581ā3585.
Acknowledgements
This work was supported in part by the Association for International Cancer Research and Cancer Research UK. SH is supported by the Portuguese Foundation for Science and Technology. We thank Dr Peter W Andrews for providing the two human embryonal carcinoma cell lines. A special thanks to Dr Peter Barber from the Neuropathology Department, University of Birmingham, The Medical School, UK.
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Honorio, S., Agathanggelou, A., Wernert, N. et al. Frequent epigenetic inactivation of the RASSF1A tumour suppressor gene in testicular tumours and distinct methylation profiles of seminoma and nonseminoma testicular germ cell tumours. Oncogene 22, 461ā466 (2003). https://doi.org/10.1038/sj.onc.1206119
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DOI: https://doi.org/10.1038/sj.onc.1206119
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