CpG island methylation in carcinoid and pancreatic endocrine tumors.
Carcinoid tumors and pancreatic endocrine tumors (PETs) are uncommon neuroendocrine neoplasms and their genetic alterations are not well characterized. CpG island methylation is a mechanism of gene silencing, and concordant methylation of multiple CpG islands as CpG island methylator phenotype (CIMP) has been described in tumors. The aim of this study was to evaluate CIMP in carcinoid tumors and PETs. We studied 16 carcinoid tumors, 11 PETs, and 22 associated normal mucosa or pancreas. Methylation status of the p14, p16, cyclo-oxygenase 2 (COX2), O(6)-methyl-guanine methyltransferase (MGMT), estrogen receptor (ER), thrombospondin 1 (THBS1), retinoic acid receptor beta 2 (RARbeta), T-type calcium channel (CACNA1G), and multiple endocrine neoplasia type-1 (MEN1) genes, and of MINT1, MINT2, MINT25, MINT27 and MINT31 loci was evaluated by methylation-specific-PCR (MSP) or combined bisulfite restriction analysis (COBRA). Carcinoid tumors were frequently methylated at RARbeta, MGMT, p16, COX2, p14, THBS1, and ER ranging from 25 to 63% of tumors. Other CpG islands were infrequently methylated or unmethylated. The adjoining normal mucosa was also methylated for ER, COX2, and RARbeta, but methylation at p14, p16, THBS1, and MGMT was tumor-specific. By contrast, PETs and normal pancreas were frequently methylated only at ER. Methylation was more frequent in carcinoid tumors than PETs at MGMT (25 versus 0%, p = 0.03), THBS1 (44 versus 9%, p = 0.04), p14 (44 versus 9%, p = 0.04) and RARbeta (25 versus 0%, p = 0.03). Loss of p16 protein expression correlated with methylation of p16 gene in carcinoid tumors (p = 0.006). Our study indicates that methylation profile of carcinoid tumors differs from PETs, reflecting different molecular pathogenesis.
Chan
Annie On-On
AO
Department of Pathology, The University of Texas M D Anderson Cancer Center, Houston 77030, USA.
Kim
Sang Geol
SG
Bedeir
Ahmed
A
Issa
Jean-Pierre
JP
Hamilton
Stanley R
SR
Rashid
Asif
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002276:Carcinoid Tumor / Q000235:genetics / Q000378:metabolism*; D002899:Chromosomes, Human, Pair 9; D018899:CpG Islands / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D019942:Genes, p16; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D015534:Trans-Activators / Q000235:genetics; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; C105373:MEN1 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051176:beta Catenin