Abstract
Deletions of chromosome 3p are frequent in many types of neoplasia including neural crest tumours such as neuroblastoma (NB) and phaeochromocytoma. Recently we isolated several candidate tumour suppressor genes (TSGs) from a 120 kb critical interval at 3p21.3 defined by overlapping homozygous deletions in lung and breast tumour lines. Although mutation analysis of candidate TSGs in lung and breast cancers revealed only rare mutations, expression of one of the genes (RASSF1A) was absent in the majority of lung tumour cell lines analysed. Subsequently methylation of a CpG island in the promoter region of RASSF1A was demonstrated in a majority of small cell lung carcinomas and to a lesser extent in non-small cell lung carcinomas. To investigate the role of 3p TSGs in neural crest tumours, we (a) analysed phaeochromocytomas for 3p allele loss (n=41) and RASSF1A methylation (n=23) and (b) investigated 67 neuroblastomas for RASSF1A inactivation. 46% of phaeochromocytomas showed 3p allele loss (38.5% at 3p21.3). RASSF1A promoter region hypermethylation was found in 22% (5/23) of sporadic phaeochromocytomas and in 55% (37/67) of neuroblastomas analysed but RASSF1A mutations were not identified. In two neuroblastoma cell lines, methylation of RASSF1A correlated with loss of RASSF1A expression and RASSF1A expression was restored after treatment with the demethylating agent 5-azacytidine. As frequent methylation of the CASP8 gene has also been reported in neuroblastoma, we investigated whether RASSF1A and CASP8 methylation were independent or related events. CASP8 methylation was detected in 56% of neuroblastomas with RASSF1A methylation and 17% without RASSF1A methylation (P=0.0031). These results indicate that (a) RASSF1A inactivation by hypermethylation is a frequent event in neural crest tumorigenesis, particularly neuroblastoma, and that RASSF1A is a candidate 3p21.3 neuroblastoma TSG and (b) a subset of neuroblastomas may be characterized by a CpG island methylator phenotype.
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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, Moher ER,, Latif F . 2001 Oncogene 20: 1509–1518
Astuti D, Douglas F, Eng C, Lennard T, Aliaganis I, Woodward ER, Evans G, Latif F, Maher ER . 2001 Lancet 357: 1181–1182
Burbee DG, Forgacs E, Zochbauer S, Shivakumar L, Gao B, Randle D, Virmani A, Bader S, Sekido Y, Latif F, Gong K. Gazdar AF, Lerman MI, White M, Minna JD . 2001 JNCI. 93: 691–699
Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP . 2000 Nat. Genet. 25: 315–319
Ejeskar K, Aburatani H, Abrahamsson J, Kogner P, Martinsson T . 1998 Br. J. Cancer 77: 1787–1791
Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HK, Lips CJ, Nishisho I, Takai SI . 1996 JAMA 276: 1575–1579
Fullwood P, Marchini S, Rader JS, Martinez A, Macartney D, Broggini M, Morelli C, Barbanti-Brodano G, Maher ER, Latif F . 1999 Cancer Res. 59: 4662–4667
Hiatt KK, Ingram DA, Zhang Y, Bollag G, Clapp DW . 2001 J. Biol. Chem. 276: 7240–7245
Hoehner JC, Hedborg F, Eriksson L, Sandstedt B, Grimelius L, Olsen L, Pahlman S . 1998 Lab. Invest. 78: 29–45
Kim ST, Lim DS, Canman CE, Kastan M.B . 1999 Biol. Chem. 274: 37538–37543
Klose A, Ahmadian MR, Schuelke M, Scheffzek K, Hoffmeyer S, Gewies A, Schmitz F, Kaufmann D, Peters H, Wittinghoferm A, Nurnberg P . 1998 Hum. Mol. Genet. 7: 1261–1268
Latif F, Tory K, Modi WS, Graziano SL, Gamble G, Douglas J, Heppell-Parton AC, Rabbitts PH, Zbar B, Lerman MI . 1992 Genes Chromosomes Cancer 5: 119–127
Lerman MI, Minna JD . for The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium. 2000 Cancer Res. 60: 6116–6133
Maris JM, Matthay KK . 1999 J. Clin. Oncol. 17: 2264–2279
Martinsson T, Sjoberg RM, Hallstensson K, Nordling M, Hedborg F, Kogner P . 1997a Eur. J. Cancer 33: 1997–2001
Martinsson T, Sjoberg RM, Hedborg F, Kogner P . 1997b Cancer Genet. Cytogenet. 95: 183–189
Moley JF, Brother MB, Wells SA, Spengler BA, Biedler JL, Brodeur GM . 1991 Cancer Res. 51: 1596–1599
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, Maher ER . 2001 Cancer Res. In press
Sundaresan V, Chung G, Heppell-Parton A, Xiong J, Grundy C, Roberts I, James L, Cahn A, Bench A, Douglas J, et al . 1998 Oncogene 17: 1723–1729
Tanaka T, Sugimoto T, Sawada T . 1998 Cancer 83: 1626–1633
Teitz T, Wei T, Valentine MB, Vanin EF, Grenet J, Valentine VA, Behmm FG, Look AT, Lahti JM, Kidd VJ . 2000 Nat. Med. 6: 529–535
Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP . 1999 Proc. Natl. Acad. Sci. USA 96: 8681–8686
Vargas MP, Zhuang Z, Wang C, Vortmeyer A, Linehan WM, Merino MJ . 1997 Hum. Pathol. 28: 411–415
Vos MD, Ellis CA, Bell A, Birrer MJ, Clark GJ . 2000 J. Biol. Chem. 275: 35669–35672
Wallace MR, Marchukm DA, Andersen LB, Letcher R, Odeh HM, Saulino AM, Fountain JW, Brereton A, Nicholson J, Mitchell AL, et al . 1990 Science 249: 181–186
Woodward ER, Eng C, McMahon R, Voutilainen R, Affara NA, Ponder BA, Maher ER . 1997 Hum. Mol. Genet. 6: 1051–1056
Zeiger MA, Zbar B, Keiser H, Linehan WM, Gnarra JR . 1995 Genes Chromosomes Cancer 13: 151–156
Acknowledgements
This work is supported in part by British Heart Foundation, Association for International Cancer Research, and Cancer Research Campaign. S Honorio is supported by Fundacao para a Ciencia e a Technologia. Drs Martinsson and Kogner supported by funds from the Swedish Cancer Society and Swedish Children's Cancer Foundation.
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Astuti, D., Agathanggelou, A., Honorio, S. et al. RASSF1A promoter region CpG island hypermethylation in phaeochromocytomas and neuroblastoma tumours. Oncogene 20, 7573–7577 (2001). https://doi.org/10.1038/sj.onc.1204968
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DOI: https://doi.org/10.1038/sj.onc.1204968
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