Epigenetic and genetic alterations in duodenal carcinomas are distinct from biliary and ampullary carcinomas.
OBJECTIVE
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), O(6)-methyl-guanine methyltransferase (MGMT), estrogen receptor (ER), retinoic acid receptor beta 2 (RAR beta), 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), RAR beta (P = 0.03), and ER (P = 0.001), and than ampullary carcinomas at RAR beta (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.
Department of Pathology, the University of Texas M. D. Anderson Cancer Center, Houston, 77030, USA.
Sang Geol
SG
Kim
Annie On-On
AO
Chan
Tsung-Teh
TT
Wu
Jean-Pierre J
JP
Issa
Stanley R
SR
Hamilton
Asif
A
Rashid
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D014670:Ampulla of Vater / Q000473:pathology*; D001661:Biliary Tract Neoplasms / Q000235:genetics* / Q000473:pathology; D015820:Cadherins; D020747:Calcium Channels, T-Type / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002899:Chromosomes, Human, Pair 9; D018899:CpG Islands; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D051546:Cyclooxygenase 2; D019175:DNA Methylation; D004379:Duodenal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D010641:Phenotype; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D011960:Receptors, Estrogen / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
C079091:APBA1 protein, human; C491636:APBA2 protein, human; C117536:APBA3 protein, human; D048868:Adaptor Proteins, Signal Transducing; C513071:Apba1 protein, rat; C485532:Apba3 protein, rat; D015820:Cadherins; D020747:Calcium Channels, T-Type; D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D007527:Isoenzymes; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D011960:Receptors, Estrogen; D018168:Receptors, Retinoic Acid; D018125:Receptors, Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; C082925:retinoic acid receptor beta; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II