Abstract
Background
Little is known about the genetic changes involved in the pathogenesis of gallbladder cancer. The aim of this study was to examine the presence of mutations in exon 15 of the B-raf gene to investigate its role in gallbladder carcinogenesis.
Materials and methods
We examined the mutational status in exon 15 of B-raf gene in 21 gallbladder carcinoma specimens and investigated its association with the presence of K-ras and p53 alterations, microsatellite instability and the clinicopathological features of tumors.
Results
B-raf mutations were observed in 7 of 21 (33%) gallbladder carcinomas examined, and all were located at the hot spot codon 599 of exon 15. K-ras and B-raf mutations were never in the same specimens.
Conclusions
B-raf gene mutations seem to be a quite common event in gallbladder carcinomas, implying that B-raf may play an important role in the pathogenesis of this tumor.
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Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, Einhorn E, Herlyn M, Minna J, Nicholson A, Roth JA, Albelda SM, Davies H, Cox C, Brignell G, Stephens P, Futreal PA, Wooster R, Stratton MR, Weber BL (2002) BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 62:6997–7000
Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B, Beller U, Westra W, Ladenson P, Sidransky D (2003) BRAF mutation in papillary thyroid carcinoma. 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, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954
Itoi T, Watanabe H, Ajioka Y, Oohashi Y, Takel K, Nishikura K, Nakamura Y, Horil A, Saito T (1996) APC, K-ras codon 12 mutations and p53 gene expression in carcinoma and adenoma of the gall-bladder suggest two genetic pathways in gall-bladder carcinogenesis. Pathol Int 46:333–340
Mercer KE, Pitchard CA (2003) Raf proteins and cancer: B-Raf is identified as a mutational target. Biochim Biophys Acta 1653:25–40
Naoki K, Chen TH, Richards WG, Sugarbaker DJ, Meyerson M (2002) Missense mutations of the BRAF gene in human lung adenocarcinoma. Cancer Res 62:7001–7003
Peyssonaux C, Eychene A (2001) The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell 93:53–62
Pitt HA, Dooley WC, Teo CJ, Cameron JL (1995) Malignancies of the biliary tree. Curr Prob Surg 32:1–90
Rajagopalan H, Bardelli A, Lengauer C, Kinzler K, Vogelstein B, Velculescu V (2002) RAF/RAS oncogenes and mismatch-repair status. Nature 418:934
Reeves ME, DeMatteo RP (2000) Genes and viruses in hepatobiliary neoplasia. Semin Surg Oncol 19:84–93
Saetta A, Lazaris Ch, Davaris PS (1996) Detection of Ras oncogenes point mutations and simultaneous proliferative fraction estimation in gallbladder cancer. Pathol Res Pract 192:532–540
Saetta A, Lazaris AC, Michalopoulos NV, Davaris PS (2001) Genetic alterations involved in the development of gallbladder carcinomas from Greek patients. Hepatogastroenterology 48:1284–1288
Sessa F, Furlan D, Genasetti A, Billo P, Feltri M, Capella C (2003) Microsatellite instability and p53 expression in gallbladder carcinomas. Diagn Mol Pathol 12:96–102
Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Witzigmann H, Hauss J, Wittekind (2003) Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut 52:706–712
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, Leung SY (2002) Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res 62:6451–6455
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Saetta, A.A., Papanastasiou, P., Michalopoulos, N.V. et al. Mutational analysis of BRAF in gallbladder carcinomas in association with K-ras and p53 mutations and microsatellite instability. Virchows Arch 445, 179–182 (2004). https://doi.org/10.1007/s00428-004-1046-9
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DOI: https://doi.org/10.1007/s00428-004-1046-9