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

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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
Externally publishedYes

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Epigenomics
Methylation
Carcinoma
Microsatellite Instability
Retinoic Acid Receptors
Estrogen Receptors
CpG Islands
Methyltransferases
Mutation
Duodenal Neoplasms
T-Type Calcium Channels
Ampulla of Vater
p16 Genes
Extrahepatic Bile Ducts
Neoplasms
Loss of Heterozygosity
Cyclooxygenase 2
Duodenum
Genes
Chromosomes

ASJC Scopus subject areas

  • Gastroenterology

Cite this

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

Epigenetic and genetic alterations in duodenal carcinomas are distinct from biliary and ampullary carcinomas. / Kim, Sang Geol; On-On Chan, Annie; Wu, Tsung Teh; Issa, Jean Pierre J; Hamilton, Stanley R.; Rashid, Asif.

In: Gastroenterology, Vol. 124, No. 5, 01.05.2003, p. 1300-1310.

Research output: Contribution to journalArticle

Kim, Sang Geol ; On-On Chan, Annie ; Wu, Tsung Teh ; Issa, Jean Pierre J ; Hamilton, Stanley R. ; Rashid, Asif. / Epigenetic and genetic alterations in duodenal carcinomas are distinct from biliary and ampullary carcinomas. In: Gastroenterology. 2003 ; Vol. 124, No. 5. pp. 1300-1310.
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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.",
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T1 - Epigenetic and genetic alterations in duodenal carcinomas are distinct from biliary and ampullary carcinomas

AU - Kim, Sang Geol

AU - On-On Chan, Annie

AU - Wu, Tsung Teh

AU - Issa, Jean Pierre J

AU - Hamilton, Stanley R.

AU - Rashid, Asif

PY - 2003/5/1

Y1 - 2003/5/1

N2 - 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.

AB - 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.

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