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Mutually exclusive NRASQ61R and BRAFV600E mutations at the single-cell level in the same human melanoma

Oncogene volume 25, pages 3357–3364 (2006)Cite this article

Abstract

Activating BRAF or NRAS mutations have been found in 80% of human sporadic melanomas, but only one of these genetic alterations could be detected in each tumour. This suggests that BRAF and NRAS ‘double mutants’ may not provide advantage for tumour growth, or may even be selected against during tumorigenesis. However, by applying mutant-allele-specific-amplification-PCR method to short-term melanoma lines, one out of 14 tumours was found to harbour both BRAFV600E and the activating NRASQ61R mutations. On the other hand, analysis of 21 melanoma clones isolated by growth in soft agar from this tumour indicated that 16/21 clones harboured a BRAFV600E, but were wild-type for NRAS, whereas the remaining had the opposite genotype (NRASQ61R/wild-type BRAF). When compared to BRAFV600E clones, NRASQ61R clones displayed reduced growth in soft agar, but higher proliferative ability in vitro in liquid medium and even in vivo after grafting into SCID/SCID mice. These data suggest that NRAS and BRAF activating mutations can coexist in the same melanoma, but are mutually exclusive at the single-cell level. Moreover, the presence of NRASQ61R or BRAFV600E is associated with distinct in vitro and in vivo growth properties of neoplastic cells.

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References

  • Anichini A, Mazzocchi A, Fossati G, Parmiani G . (1989). J Immunol 142: 3692–3701.

  • Ball NJ, Yohn JJ, Morelli JG, Norris DA, Golitz LE, Hoeffler JP . (1994). J Invest Dermatol 102: 285–290.

  • Bhowmick NA, Moses HL . (2005). Curr Opin Genet Dev 15: 97–101.

  • Bloethner S, Chen B, Hemminki K, Muller-Berghaus J, Ugurel S, Schadendorf D et al. (2005). Carcinogenesis 26: 1224–1232.

  • Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R et al. (2002). Cancer Res 62: 6997–7000.

  • Daniotti M, Oggionni M, Ranzani T, Vallacchi V, Campi V, Di Stasi D et al. (2004). Oncogene 23: 5968–5977.

  • Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S et al. (2002). Nature 417: 949–954.

  • Downward J . (2004). Oncogene 23: 8376–8383.

  • Garnett MJ, Marais R . (2004). Cancer Cell 6: 313–319.

  • Gorden A, Osman I, Gai W, He D, Huang W, Davidson A et al. (2003). Cancer Res 63: 3955–3957.

  • Gray-Schopfer VC, da Rocha Dias S, Marais R . (2005). Cancer Metastasis Rev 24: 165–183.

  • Hasegawa Y, Takeda S, Ichii S, Koizumi K, Maruyama M, Fujii A et al. (1995). Oncogene 10: 1441–1445.

  • Hendrix MJ, Seftor EA, Kirschmann DA, Quaranta V, Seftor RE . (2003). Ann NY Acad Sci 995: 151–161.

  • Jiveskog S, Ragnarsson-Olding B, Platz A, Ringborg U . (1998). J Invest Dermatol 111: 757–761.

  • Joyce JA . (2005). Cancer Cell 7: 513–520.

  • Lilleberg SL, Durocher J, Sanders C, Walters K, Culver K . (2004). Ann NY Acad Sci 1022: 250–256.

  • Linard B, Bezieau S, Benlalam H, Labarriere N, Guilloux Y, Diez E et al. (2002). J Immunol 168: 4802–4808.

  • Loewe R, Kittler H, Fischer G, Fae I, Wolff K, Petzelbauer P . (2004). J Invest Dermatol 123: 733–736.

  • Lozupone F, Pende D, Burgio VL, Castelli C, Spada M, Venditti M et al. (2004). Cancer Res 64: 378–385.

  • Lupetti R, Sensi M, Mortarini R, Anichini A, Clemente C, Parmiani G . (1994). Melanoma Res 4: 11–19.

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

  • Mercer KE, Pritchard CA . (2003). Biochim Biophys Acta 1653: 25–40.

  • Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM et al. (2005). Nature 436: 720–724.

  • Miller CJ, Cheung M, Sharma A, Clarke L, Helm K, Mauger D et al. (2004). J Invest Dermatol 123: 990–992.

  • Omholt K, Platz A, Kanter L, Ringborg U, Hansson J . (2003). Clin Cancer Res 9: 6483–6488.

  • Pavey S, Johansson P, Packer L, Taylor J, Stark M, Pollock PM et al. (2004). Oncogene 23: 4060–4067.

  • Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM et al. (2003). Nat Genet 33: 19–20.

  • Rak J, Yu JL . (2004). Semin Cancer Biol 14: 93–104.

  • Repasky GA, Chenette EJ, Der CJ . (2004). Trends Cell Biol 14: 639–647.

  • Satyamoorthy K, Li G, Gerrero MR, Brose MS, Volpe P, Weber BL et al. (2003). Cancer Res 63: 756–759.

  • Sebolt-Leopold JS, Herrera R . (2004). Nat Rev Cancer 4: 937–947.

  • Sivertsson A, Platz A, Hansson J, Lundeberg J . (2002). Clin Chem 48: 2164–2170.

  • Smalley KS . (2003). Int J Cancer 10: 527–532.

  • Sparman A, Bar-Sagi D . (2004). Cancer Cell 6: 447–457.

  • Strumberg D, Richly H, Hilger RA, Schleucher N, Korfee S, Tewes M et al. (2005). J Clin Oncol 23:965–972.

  • Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM et al. (2004). Cell 116: 855–867.

  • Watnick RS, Cheng YN, Rangarajan A, Ince TA, Weinberg RA . (2003). Cancer Cell 3: 219–231.

  • Wellbrock C, Karasarides M, Marais R . (2004). Nat Rev Mol Cell Biol 5: 875–885.

  • Xu X, Quiros RM, Gattuso P, Ain KB, Prinz RA . (2003). Cancer Res 63: 4561–4567.

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Acknowledgements

We gratefully acknowledge the contributions of Donata Penso for sequence analysis. This work was partially supported by Grants from the Italian Association for Cancer Research (AIRC, Milan), the Ministry of Health (Rome), Compagnia di S Paolo (Turin).

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Authors and Affiliations

  1. Department of Experimental Oncology, Human Tumor Immunobiology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy

    M Sensi, G Nicolini, C Petti, I Bersani, A Molla, C Vegetti, R Mortarini & A Anichini

  2. Department of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy

    F Lozupone & S Fais

  3. Department of Drug Research and Evaluation Pharmacogenetic, Drug Resistance and Experimental Therapeutic Section, Istituto Superiore di Sanità, Milano, Rome, Italy

    D Nonaka

  4. Unit of Immunotherapy of Human Tumors, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy

    G Parmiani

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  1. M Sensi
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  2. G Nicolini
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Correspondence to M Sensi.

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Sensi, M., Nicolini, G., Petti, C. et al. Mutually exclusive NRASQ61R and BRAFV600E mutations at the single-cell level in the same human melanoma. Oncogene 25, 3357–3364 (2006). https://doi.org/10.1038/sj.onc.1209379

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