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CpG island promoter hypermethylation of the Ras-effector gene NORE1A occurs in the context of a wild-type K-ras in lung cancer

Oncogene volume 23, pages 8695–8699 (2004)Cite this article

Abstract

Imbalance of the Ras signaling pathway is a major hallmark of human cancer. In this context, activating point mutations of the K-ras oncogene are a common feature of many tumor types. The discovery of methylation-mediated silencing of the Ras-effector homologue RASSF1A has revealed another way by which this cellular pathway may be altered. Inactivation by hypermethylation of a RASSF1A homologue, NORE1A, has recently been observed in human cancers. If both K-ras and NORE1A act in the same pathway, simultaneous molecular lesions in the two genes in the same tumor should be a rare event. To test whether this inverse association exists, we have analysed the K-ras mutational status and NORE1A CpG island hypermethylation of 61 non-small-cell lung carcinomas and the methylation status of the two other Ras effectors, RASSF1A and HRASLS. No association was found between the methylation status of NORE1A, RASSF1A and HRASLS or the status of K-ras with respect to the latter two genes. However, our results demonstrate that the epigenetic alteration of NORE1A is confined to lung tumors with a wild-type K-ras: 88% (15 of 17) of the tumors with NORE1 hypermethylation did not harbor a K-ras mutation (P=0.008, Fisher's exact test). Thus, the mutual exclusivity of the epigenetic and genetic alterations in the two genes of the Ras pathway suggests that they play a critical and cooperative role in human tumorigenesis.

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References

  • Akiyama H, Hiraki Y, Noda M, Shigeno C, Ito H and Nakamura T . (1999). J. Biol. Chem., 274, 32192–32197.

  • Aoyama Y, Avruch J and Zhang XF . (2004). Oncogene 2004 Mar 8 [Epub ahead of print].

  • 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, 691–699.

  • Chen H, Toyooka S, Gazdar AF and Hsieh JT . (2003). J. Biol. Chem., 278, 3121–3130.

  • Dammann R, Li C, Yoon JH, Chin PL, Bates S and Pfeifer GP . (2000). Nat. Genet., 25, 315–319.

  • Dammann R, Schagdarsurengin U, Liu L, Otto N, Gimm O, Dralle H, Boehm BO, Pfeifer GP and Hoang-Vu C . (2003). Oncogene, 22, 3806–3812.

  • Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR and Futreal PA . (2002). Nature, 417, 949–954.

  • 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, 7504–7509.

  • Esteller M, Cordon-Cardo C, Corn PG, Meltzer SJ, Pohar KS, Watkins DN, Capella G, Peinado MA, Matias-Guiu X, Prat J, Baylin SB and Herman JG . (2001). Cancer Res., 61, 2816–2821.

  • Esteller M, Tortola S, Toyota M, Capella G, Peinado MA, Baylin SB and Herman JG . (2000). Cancer Res., 60, 129–133.

  • Hainaut P, Soussi T, Shomer B, Hollstein M, Greenblatt M, Hovig E, Harris CC and Montesano R . (1997). Nucleic Acids Res., 25, 151–157.

  • Herman JG, Graff JR, Myohanen S, Nelkin BD and Baylin SB . (1996). Proc. Natl. Acad. Sci. USA, 93, 9821–9826.

  • Hesson L, Dallol A, Minna JD, Maher ER and Latif F . (2003). Oncogene, 22, 947–954.

  • Ito H, Akiyama H, Shigeno C and Nakamura T . (2001). Cytogenet. Cell Genet., 93, 36–39.

  • Kaneda A, Kaminishi M, Yanagihara K, Sugimura T and Ushijima T . (2002). Cancer Res., 62, 6645–6650.

  • Khokhlatchev A, Rabizadeh S, Xavier R, Nedwidek M, Chen T, Zhang XF, Seed B and Avruch J . (2002). Curr. Biol., 12, 253–265.

  • Kim DH, Kim JS, Park JH, Lee SK, Ji YI, Kwon YM, Shim YM, Han J and Park J . (2003). Cancer Res., 63, 6206–6211.

  • Malumbres M and Barbacid M . (2003). Nat. Rev. Cancer, 3, 459–465.

  • Minna JD, Roth JA and Gazdar AF . (2002). Cancer Cell, 1, 49–52.

  • Morris MR, Hesson LB, Wagner KJ, Morgan NV, Astuti D, Lees RD, Cooper WN, Lee J, Gentle D, Macdonald F, Kishida T, Grundy R, Yao M, Latif F and Maher ER . (2003). Oncogene, 22, 6794–8601.

  • Ortiz-Vega S, Khokhlatchev A, Nedwidek M, Zhang XF, Dammann R, Pfeifer GP and Avruch J . (2002). Oncogene, 21, 1381–1390.

  • Ponting CP and Benjamin DR . (1996). Trends Biochem. Sci., 21, 422–425.

  • Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B and Velculescu VE . (2002). Nature, 418, 934.

  • Ramirez JL, Sarries C, de Castro PL, Roig B, Queralt C, Escuin D, de Aguirre I, Sanchez JM, Manzano JL, Margeli M, Sanchez JJ, Astudillo J, Taron M and Rosell R . (2003). Cancer Lett., 193, 207–216.

  • Sanchez-Cespedes M, Ahrendt SA, Piantadosi S, Rosell R, Monzo M, Wu L, Westra WH, Yang SC, Jen J and Sidransky D . (2001). Cancer Res., 61, 1309–1313.

  • Schimanski CC, Linnemann U and Berger MR . (1999). Cancer Res., 59, 5169–5175.

  • Serrano M . (1997). Exp. Cell Res., 237, 7–13.

  • Soares P, Trovisco V, Rocha AS, Lima J, Castro P, Preto A, Maximo V, Botelho T, Seruca R and Sobrinho-Simoes M . (2003). Oncogene, 22, 4578–4580.

  • Sparks AB, Morin PJ, Vogelstein B and Kinzler KW . (1998). Cancer Res., 58, 1130–1134.

  • Tommasi S, Dammann R, Jin SG, Zhang Xf XF, Avruch J and Pfeifer GP . (2002). Oncogene, 21, 2713–2720.

  • van Engeland M, Roemen GM, Brink M, Pachen MM, Weijenberg MP, de Bruine AP, Arends JW, van den Brandt PA, de Goeij AF and Herman JG . (2002). Oncogene, 21, 3792–3795.

  • Vavvas D, Li X, Avruch J and Zhang XF . (1998). J. Biol. Chem., 273, 5439–5442.

  • Virmani AK, Fong KM, Kodagoda D, McIntire D, Hung J, Tonk V, Minna JD and Gazdar AF . (1998). Genes Chromosomes Cancer, 21, 308–319.

  • Vos MD, Ellis CA, Bell A, Birrer MJ and Clark GJ . (2000). J. Biol. Chem., 275, 35669–35672.

  • Vos MD, Martinez A, Ellis CA, Vallecorsa T and Clark GJ . (2003). J. Biol. Chem., 278, 21938–21943.

  • Xing M, Cohen Y, Mambo E, Tallini G, Udelsman R, Ladenson PW and Sidransky D . (2004). Cancer Res., 64, 1664–1668.

  • Zhu K, Hamilton AD and Sebti SM . (2003). Curr. Opin. Invest. Drugs, 4, 1428–1435.

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Authors and Affiliations

  1. Molecular Pathology Program, Cancer Epigenetics Laboratory, Spanish National Cancer Centre (CNIO), Melchor Fernandez Almagro 3, Madrid, 28029, Spain

    Manuel Irimia, Mario F Fraga & Manel Esteller

  2. Lung Cancer Research Group, Molecular Pathology Program, Spanish National Cancer Centre (CNIO), Melchor Fernandez Almagro 3, Madrid, 28029, Spain

    Montserrat Sanchez-Cespedes

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  1. Manuel Irimia
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  2. Mario F Fraga
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  4. Manel Esteller
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Correspondence to Manel Esteller.

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Irimia, M., Fraga, M., Sanchez-Cespedes, M. et al. CpG island promoter hypermethylation of the Ras-effector gene NORE1A occurs in the context of a wild-type K-ras in lung cancer. Oncogene 23, 8695–8699 (2004). https://doi.org/10.1038/sj.onc.1207914

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