Abstract
Activation of the Raf/MEK/ERK (MAPK) signal transduction cascade by RAS mutations has been found in a variety of human cancers. Mutations of BRAF provide an alternative route for activation of this signalling pathway. To determine the role of mutations in BRAF and KRAS2 in the neoplastic progression of Barrett's adenocarcinoma, we analysed both genes for common mutations. After microdissection, DNA of 19 Barrett's adenocarcinomas, 56 Barrett's intraepithelial neoplasias (n=29 low-grade intraepithelial neoplasia (LGIN) and n=27 high-grade intraepithelial neoplasia (HGIN)), 30 Barrett's mucosa without neoplasia and normal squamous, as well as gastric epithelium, were analysed for BRAF and KRAS2 mutation. Activating BRAF mutations were identified in 2/19 Barrett's adenocarcinomas (11%) and in 1/27 HGIN (4%). KRAS2 mutations were found in four out of 19 (21%) Barrett's adenocarcinomas examined and in three cases of HGIN (11%). In LGIN as well as in normal gastric or oesophageal mucosa, neither BRAF nor KRAS2 mutations were detected. All lesions with KRAS2 mutations had an intact BRAF gene. The status of mismatch-repair proteins was neither related to BRAF nor KRAS2 mutations. These data indicate that RAS or BRAF mutations are detected in about 32% of all Barrett's adenocarcinomas. We conclude that the disruption of the Raf/MEK/ERK (MAPK) kinase pathway is a frequent but also early event in the development of Barrett's adenocarcinoma.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aguirre-Ghiso JA, Estrada Y, Liu D and Ossowski L . (2003). Cancer Res., 63, 1684–1695.
Arber N, Shapira I, Ratan J, Stern B, Hibshoosh H, Moshkowitz M, Gammon M, Fabian I and Halpern Z . (2000). Gastroenterology, 118, 1045–1050.
Barrett MT, Sanchez CA, Galipeau PC, Neshat K, Emond M and Reid BJ . (1996). Oncogene, 13, 1867–1873.
Barrett MT, Sanchez CA, Prevo LJ, Wong DJ, Galipeau PC, Paulson TG, Rabinovitch PS and Reid BJ . (1999). Nat. Genet., 22, 106–109.
Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B, Beller U, Westra WH, Ladenson PW and Sidransky D . (2003). J. Natl. Cancer Inst., 95, 625–627.
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.
Dong J, Phelps RG, Qiao R, Yao S, Benard O, Ronai Z and Aaronson SA . (2003). Cancer Res., 63, 3883–3885.
Dunn JR, Risk JM, Langan JE, Marlee D, Ellis A, Campbell F, Watson AJ and Field JK . (2003). Oncogene, 22, 4134–4142.
Fitzgerald RC . (2003). Gut, 52, 16–17.
Hakimi MA, Bochar DA, Chenoweth J, Lane WS, Mandel G and Shiekhattar R . (2002). Proc. Natl. Acad. Sci. USA, 99, 7420–7425.
Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE and Fagin JA . (2003). Cancer Res., 63, 1454–1457.
Leder A, Lebel M, Zhou F, Fontaine K, Bishop A and Leder P . (2002). Oncogene, 21, 6657–6668.
Liao Y, Satoh T, Gao X, Jin TG, Hu CD and Kataoka T . (2001). J. Biol. Chem., 276, 28478–28483.
Mercer KE and Pritchard CA . (2003). Biochim. Biophys. Acta, 1653, 25–40.
Morales CP, Souza RF and Spechler SJ . (2002). Lancet, 360, 1587–1589.
Naoki K, Chen TH, Richards WG, Sugarbaker DJ and Meyerson M . (2002). Cancer Res., 62, 7001–7003.
Peyssonnaux C and Eychene A . (2001). Biol. Cell, 93, 53–62.
Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins C, Moses TY, Hostetter G, Wagner U, Kakareka J, Salem G, Pohida T, Heenan P, Duray P, Kallioniemi O, Hayward NK, Trent JM and Meltzer PS . (2003). Nat. Genet., 33, 19–20 (Epub 2002 Nov 25).
Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B and Velculescu VE . (2002). Nature, 29, 934.
Rüschoff J, Dietmaier W, Bocker T, Wallinger S, Kullmann F, Beham A and Hofstadter F . (1998). Pathologe, 19, 269–278.
Satyamoorthy K, Li G, Gerrero MR, Brose MS, Volpe P, Weber BL, Van Belle P, Elder DE and Herlyn M . (2003). Cancer Res., 63, 756–759.
Singer G, Oldt III R, Cohen Y, Wang BG, Sidransky D, Kurman RJ and Shih IeM . (2003). J. Natl. Cancer Inst., 95, 484–486.
Smalley KS . (2003). Int. J. Cancer, 104, 527–532.
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.
Spechler SJ . (2002). N. Engl. J. Med., 346, 836–842.
Stahl J . (2000). Adv. Anat. Pathol., 7, 85–93.
Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Witzigmann H, Hauss J and Wittekind C . (2003). Gut, 52, 706–712.
Tselepis C, Perry I, Dawson C, Hardy R, Darnton SJ, McConkey C, Stuart RC, Wright N, Harrison R and Jankowski JA . (2002). Oncogene, 21, 6071–6081.
Weber A, Langhanki L, Sommerer F, Markwarth A, Wittekind C and Tannapfel A . (2003). Oncogene, 22, 4757–4759.
Weber CK, Slupsky JR, Kalmes HA and Rapp UR . (2001). Cancer Res., 61, 3595–3598.
WHO (2000). Pathology and Genetics. Hamilton SR, Aaltonen LA (eds) IARC Press: Lyon, pp. 173–200.
Yuen ST, Davies H, Chan TL, Ho JW, Bignell GR, Cox C, Stephens P, Edkins S, Tsui WW, Chan AS, Futreal PA, Stratton MR, Wooster R and Leung SY . (2002). Cancer Res., 62, 6451–6455.
Acknowledgements
This paper was supported by the Bundesministerium für Bildung und Forschung (BMB+F), Interdisciplinary Centre for Clinical Research (IZKF) at the University of Leipzig (01KS9504/1, project D01).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sommerer, F., Vieth, M., Markwarth, A. et al. Mutations of BRAF and KRAS2 in the development of Barrett's adenocarcinoma. Oncogene 23, 554–558 (2004). https://doi.org/10.1038/sj.onc.1207189
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.onc.1207189
Keywords
This article is cited by
-
Analysis of immune related gene expression profiles and immune cell components in patients with Barrett esophagus
Scientific Reports (2022)
-
An Integrative Pharmacogenomic Approach Identifies Two-drug Combination Therapies for Personalized Cancer Medicine
Scientific Reports (2016)
-
Characterization of a Novel Tumorigenic Esophageal Adenocarcinoma Cell Line: OANC1
Digestive Diseases and Sciences (2014)
-
Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity
Nature Genetics (2013)
-
Vemurafenib: the first drug approved for BRAF-mutant cancer
Nature Reviews Drug Discovery (2012)
