Epigenetic and genetic alterations in duodenal carcinomas are distinct from biliary and ampullary carcinomas

Sang Geol Kim, Annie On-On Chan, Tsung Teh Wu, Jean Pierre J. Issa, Stanley R. Hamilton, Asif Rashid

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Background & Aims: Carcinomas of the extrahepatic bile ducts, ampulla of Vater, and duodenum are uncommon, and their epigenetic and genetic alterations are not well characterized. Methods: We therefore compared the methylation profile and genetic alterations in 18 extrahepatic biliary, 9 ampullary, and 12 duodenal carcinomas. We evaluated methylation at p16, p14, and human Mut L homologue (hMLH1) by methylation-specific PCR (MSP), and at cyclooxygenase 2 (COX2), O6-methylguanine methyltransferase (MGMT), estrogen receptor (ER), retinoic acid receptor β2 (RARβ), and T-type calcium channel (CACNA1G) genes, and methylated in tumor 1 (MINT1), MINT2, MINT25, MINT27, and MINT31 loci by combined bisulfite restriction analysis (COBRA); mutation of K-ras, p53, p16, and p14 genes by sequencing; loss of heterozygosity of chromosome 9p; and microsatellite instability (MSI). Results: Duodenal carcinomas were methylated more frequently or had increased methylation densities than biliary carcinomas at p14 (P = 0.04), hMLH1 (P = 0.04), MGMT (P = 0.01), MINT1 (P = 0.01), MINT25 (P = 0.01), MINT27 (P = 0.001), RARβ (P = 0.03), and ER (P = 0.001), and than ampullary carcinomas at RARβ (P = 0.02) and ER (P = 0.03). In contrast, the methylation profiles of biliary and ampullary carcinomas were not statistically different. Simultaneous methylation of 3 or more CpG islands (CpG island methylator phenotype-high) was more common in duodenal cancers (P = 0.004). MGMT methylation was associated with G-to-A mutation in K-ras (P = 0.006), and hMLH1 methylation was associated with MSI-high (P = 0.01). Conclusions: Our findings indicate that the methylation profile and genetic alterations of duodenal carcinomas are distinct from biliary and ampullary carcinomas, and that tumor-specific methylation is associated with gene mutation and MSI.

Original languageEnglish (US)
Pages (from-to)1300-1310
Number of pages11
JournalGastroenterology
Volume124
Issue number5
DOIs
StatePublished - May 1 2003

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Kim, S. G., On-On Chan, A., Wu, T. T., Issa, J. P. J., Hamilton, S. R., & Rashid, A. (2003). Epigenetic and genetic alterations in duodenal carcinomas are distinct from biliary and ampullary carcinomas. Gastroenterology, 124(5), 1300-1310. https://doi.org/10.1016/S0016-5085(03)00278-6