Gallbladder cancer is a rare malignancy and presents a poor prognosis. MYC and p53 have been implicated in gallbladder carcinogenesis. However, little is known about the molecular mechanisms involved in their regulation in this neoplasia. Here, we evaluated the MYC and TP53 copy numbers in gallbladder tumors and their possible association with protein expression. We also investigated whether MYC may be controlled by mutations and DNA promoter methylation. In the present study, 15 samples of invasive gallbladder carcinomas and six control samples were analyzed. On the other hand, the expression of MYC and p53 was more frequent in gallbladder carcinomas than in control samples (p = 0.002, p = 0.046, respectively). Gain of copies of the MYC and TP53 genes was detected in 86.7 and 50 % of gallbladder carcinomas, respectively. MYC and TP53 amplifications were associated with immunoreactivity of their protein (p = 0.029, p = 0.001, respectively). MYC hypomethylation was only detected in tumoral samples and was associated with its protein expression (p = 0.029). MYC mutations were detected in 80 % of tumor samples. The G allele at rs117856857 was associated with the presence of gallbladder tumors (p = 0.019) and with MYC expression (p = 0.044). Moreover, two tumors presented a pathogenic mutation in MYC exon 2 (rs28933407). Our study highlights that the gain of MYC and TP53 copies seems to be a frequent finding in gallbladder cancer. In addition, gain of copies, hypomethylation and point mutations at MYC may contribute to overexpression of its protein in this type of cancer.
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This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; MCS and RRB) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; MFL) as grants and fellowship awards.
Liu Z, Jiang L, Yang B, Liao D. The roles of VEGF and C-myc in occurrence, development and metastasis of gallbladder carcinoma. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2003;20(1):68–70.PubMedGoogle Scholar
Roa I, Araya JC, Shiraishi T, et al. Gallbladder carcinoma: expression of the c-myc and ras-p-21 oncogene products. Rev Med Chil. 1994;122(7):754–9.PubMedGoogle Scholar
Yukawa M, Fujimori T, Hirayama D, et al. Expression of oncogene products and growth factors in early gallbladder cancer, advanced gallbladder cancer, and chronic cholecystitis. Hum Pathol. 1993;24(1):37–40.CrossRefPubMedGoogle Scholar
Ooi A, Suzuki S, Nakazawa K, et al. Gene amplification of Myc and its coamplification with ERBB2 and EGFR in gallbladder adenocarcinoma. Anticancer Res. 2009;29(1):19–26.PubMedGoogle Scholar
Shu GS, Lv F, Yang ZL, Miao XY. Immunohistochemical study of PUMA, c-Myb and p53 expression in the benign and malignant lesions of gallbladder and their clinicopathological significances. Int J Clin Oncol. 2013;18(4):641–50. doi:10.1007/s10147-012-0431-7.CrossRefPubMedGoogle Scholar
Sessa F, Furlan D, Genasetti A, Billo P, Feltri M, Capella C. Microsatellite instability and p53 expression in gallbladder carcinomas. Diagn Mol Pathol. 2003;12(2):96–102.CrossRefPubMedGoogle Scholar
Oohashi Y, Watanabe H, Ajioka Y, Hatakeyama K. p53 immunostaining distinguishes malignant from benign lesions of the gall-bladder. Pathol Int. 1995;45(1):58–65.CrossRefPubMedGoogle Scholar
Sobin LH, Gopodarowicz MK, Wittekind C. TNM classification of malignant tumors. 7th ed. Oxford: Wiley-Blackwell; 2009.Google Scholar
Calcagno DQ, Leal MF, Seabra AD, et al. Interrelationship between chromosome 8 aneuploidy, C-MYC amplification and increased expression in individuals from northern Brazil with gastric adenocarcinoma. World J Gastroenterol. 2006;12(38):6207–11.CrossRefPubMedPubMedCentralGoogle Scholar
Yemelyanova A, Vang R, Kshirsagar M, et al. Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis. Mod Pathol. 2011;24(9):1248–53. doi:10.1038/modpathol.2011.85.CrossRefPubMedGoogle Scholar
Itoi T, Watanabe H, Yoshida M, Ajioka Y, Nishikura K, Saito T. Correlation of p53 protein expression with gene mutation in gall-bladder carcinomas. Pathol Int. 1997;47(8):525–30.CrossRefPubMedGoogle Scholar
Gustafsson U, Einarsson C, Eriksson LC, Gadaleanu V, Sahlin S, Tribukait B. DNA ploidy and S-phase fraction in carcinoma of the gallbladder related to histopathology, number of gallstones and survival. Anal Cell Pathol. 2001;23(3–4):143–52.CrossRefPubMedPubMedCentralGoogle Scholar
Futakawa N, Kimura W, Ando H, Muto T, Esaki Y. Heterogeneity of DNA ploidy pattern in carcinoma of the gallbladder: primary and metastatic sites. Jpn J Cancer Res. 1997;88(9):886–94.CrossRefPubMedGoogle Scholar
Yamamoto M, Oda N, Tahara E. DNA ploidy patterns in gallbladder adenocarcinoma. Jpn J Clin Oncol. 1990;20(1):83–6.PubMedGoogle Scholar
Rosal-Texeira C, Leal MF, Calcagno DQ et al. MYC deregulation in gastric cancer and its clinicopathological implications. PLoS ONE. 2013;8(5):e64420.Google Scholar
Fang JY, Zhu SS, Xiao SD, et al. Studies on the hypomethylation of c-myc, c-Ha-ras oncogenes and histopathological changes in human gastric carcinoma. J Gastroenterol Hepatol. 1996;11(11):1079–82.CrossRefPubMedGoogle Scholar
Fang JY, Xiao SD, Zhu SS, Yuan JM, Qiu DK, Jiang SJ. Relationship of plasma folic acid and status of DNA methylation in human gastric cancer. J Gastroenterol. 1997;32(2):171–5.CrossRefPubMedGoogle Scholar
Weng YR, Sun DF, Fang JY, Gu WQ, Zhu HY. Folate levels in mucosal tissue but not methylenetetrahydrofolate reductase polymorphisms are associated with gastric carcinogenesis. World J Gastroenterol. 2006;12(47):7591–7.CrossRefPubMedPubMedCentralGoogle Scholar