Abstract
Testicular germ cell tumours are classified into two major histological subgroups, seminomas and nonseminomas. All tumours display several recurrent chromosomal aberrations, but few target genes have been identified. Previous studies have shown that genome-wide hypermethylation of CpG islands is significantly more prevalent in nonseminomas than in seminomas. We have studied two potential target genes in testicular cancer. A series of 70 tumours were analysed for methylation of CpG sites in the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter, and in exon 1α of the cyclin-dependent kinase inhibitor 2A gene (CDKN2A). In addition, eight microsatellite markers within and flanking these genes at chromosome arms 10q and 9p, respectively, were analysed for allelic imbalances. Allele alterations were frequently seen at 9p loci (47 out of 70, 67%), but none of the tumours (none out of 55) showed methylation of CDKN2A. On the other hand, a high frequency of MGMT promoter methylation (32 out of 69, 46%) was found, as well as allelic imbalances at 10q markers (50 out of 70, 71%). A significantly higher methylation frequency was found in nonseminomas (24 out of 35, 69%) compared to seminomas (eight out of 33, 24%) (P=0.0003, Fisher's exact test). Immunohistochemical analysis of the MGMT protein in a subgroup (n=20) of the testicular tumours supported the hypothesis of gene silencing being the functional consequence of the promoter methylation. In summary, our data suggest that inactivation of MGMT contributes to development of nonseminomatous testicular cancer.
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References
Atkin NB, Baker MC . 1982 Lancet 2: 1349
Baylin SB, Herman JG . 2000 Trends Genet. 16: 168–174
Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP . 1998 Advances in Cancer Research Vol. 72: Klein G and Van de Woude GF (eds) San Diego, CA: Academic Press pp 141–196
Bearzatto A, Szadkowski M, Macpherson P, Jiricny J, Karran K . 2000 Cancer Res. 60: 3262–3270
Castedo SM, de Jong B, Oosterhuis JW, Seruca R, Idenburg VJ, Dam A, te Meerman G, Koops HS, Sleijfer DT . 1989a Cancer Res. 49: 5696–5701
Castedo SM, de Jong B, Oosterhuis JW, Seruca R, te Meerman GJ, Dam A, Schraffordt Koops H . 1989b Cancer Res. 49: 439–443
Chaubert P, Guillou L, Kurt AM, Bertholet MM, Metthez G, Leisinger HJ, Bosman F, Shaw P . 1997 Am. J. Pathol. 151: 859–865
Costello JF, Fruhwald MC, Smiraglia DJ, Rush LJ, Robertson GP, Gao X, Wright FA, Feramisco JD, Peltomaki P, Lang JC, Schuller DE, Yu L, Bloomfield CD, Caligiuri MA, Yates A, Nishikawa R, Su Huang H, Petrelli NJ, Zhang X, O'Dorisio MS, Held WA, Cavenee WK, Plass C . 2000 Nat. Genet. 24: 132–138
Costello JF, Futscher BW, Tano K, Graunke DM, Pieper RO . 1994 J. Biol. Chem. 269: 17228–17237
Danam RP, Qian XC, Howell SR, Brent TP . 1999 Mol. Carcinog. 24: 85–89
Esteller M . 2000 Eur. J. Cancer 36: 2294–2300
Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB, Herman JG . 2000 N. Engl. J. Med. 343: 1350–1354
Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG . 1999 Cancer Res. 59: 793–797
Faulkner SW, Leigh DA, Oosterhuis JW, Roelofs H, Looijenga LH, Friedlander ML . 2000 Br. J. Cancer 83: 729–736
Harris LC, Remack JS, Brent TP . 1994 Nucl. Acids Res. 22: 4614–4619
Heidenreich A, Gaddipati JP, Moul JW, Srivastava S . 1998 J. Urol. 159: 1725–1730
Heidenreich A, Srivastava S, Moul JW, Hofmann R . 2000 Eur. Urol. 37: 121–135
Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB . 1996 Proc. Natl. Acad. Sci. USA 93: 9821–9826
Herman JG, Merlo A, Mao L, Lapidus RG, Issa JP, Davidson NE, Sidransky D, Baylin SB . 1995 Cancer Res. 55: 4525–4530
Hui R, Macmillan RD, Kenny FS, Musgrove EA, Blamey RW, Nicholson RI, Robertson JF, Sutherland RL . 2000 Clin. Cancer Res. 6: 2777–2787
Josefsen D, Ous S, Hoie J, Stenwig AE, Fosså SD . 1993 Br. J. Cancer 67: 568–572
Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day III RS, Johnson BE, Skolnick MH . 1994 Science 264: 436–440
Kraggerud SM, Skotheim RI, Szymanska J, Eknæs M, Fosså SD, Stenwig AE, Peltomaki P, Lothe RA . 2002 Genes Chrom. Cancer 34: 168–174
Looijenga LH, de Munnik H, Oosterhuis JW . 1999 Int. J. Cancer 83: 809–814
Lothe RA, Hastie N, Heimdal K, Fosså SD, Stenwig AE, Børresen AL . 1993 Genes Chrom. Cancer 7: 96–101
Matin A, Collin GB, Asada Y, Varnum D, Nadeau JH . 1999 Nat. Genet. 23: 237–240
Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB, Sidransky D . 1995 Nat. Med. 1: 686–692
Mertens F, Johansson B, Hoglund M, Mitelman F . 1997 Cancer Res. 57: 2765–2780
Mostofi FK, Sobin LH . 1976 World Health Organization: Geneva No. 16 1–39
Murty VV, Bosl GJ, Houldsworth J, Meyers M, Mukherjee AB, Reuter V, Chaganti RS . 1994 Oncogene 9: 2245–2251
Murty VV, Chaganti RS . 1998 Semin. Oncol. 25: 133–144
Nakamura M, Watanabe T, Yonekawa Y, Kleihues P, Ohgaki H . 2001 Carcinogenesis 22: 1715–1719
Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA . 1994 Nature 368: 753–756
Oosterhuis JW, Castedo SM, de Jong B, Cornelisse CJ, Dam A, Sleijfer DT, Schraffordt Koops H . 1989 Lab. Invest. 60: 14–21
Pegg AE, Dolan ME, Moschel RC . 1995 Prog. Nucleic Acids Res. Molec. Biol. 51: 167–223
Preuss I, Thust R, Kaina B . 1996 Int. J. Cancer 65: 506–512
Qian X, von Wronski MA, Brent TP . 1995 Carcinogenesis 16: 1385–1390
Qian XC, Brent TP . 1997 Cancer Res. 57: 3672–3677
Serrano M, Hannon GJ, Beach D . 1993 Nature 366: 704–707
Shim YH, Kang GH, Ro JY . 2000 Lab. Invest. 80: 689–695
Skotheim RI, Kraggerud SM, Fosså SD, Stenwig AE, Gedde-Dahl Jr T, Danielsen HE, Jakobsen KS, Lothe RA . 2001a Neoplasia 3: 196–203
Skotheim RI, Diep CB, Kraggerud SM, Jakobsen KS, Lothe RA . 2001b Cancer Genet. Cytogenet. 127: 64–70
Skotheim RI, Monni O, Mousses S, Fosså SD, Kallioniemi OP, Lothe RA, Kallioniemi A . 2002 Cancer Res. 62: 2359–2364
Smiraglia D, Fruhwald MC, Costello JF, McCormick SP, Dai Z, Peltomaki P, O'Dorisio MS, Cavenee WK, Plass C . 1999 Genomics 58: 254–262
Smiraglia D, Szymanska J, Kraggerud SM, Lothe RA, Peltomäki P, Plass C . 2002 Oncogene 21: 3909–3916
Acknowledgements
GE Lind and RI Skotheim are Research Fellows of Norwegian Cancer Society and Research Council of Norway respectively. The study was supported by additional grants from Norwegian Cancer Society (B Smith-Sørensen and RA Lothe).
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Smith-Sørensen, B., Lind, G., Skotheim, R. et al. Frequent promoter hypermethylation of the O6-Methylguanine-DNA Methyltransferase (MGMT) gene in testicular cancer. Oncogene 21, 8878–8884 (2002). https://doi.org/10.1038/sj.onc.1205978
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DOI: https://doi.org/10.1038/sj.onc.1205978
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