Chan Annie On-On, Kim Sang Geol, Bedeir Ahmed, Issa Jean-Pierre, Hamilton Stanley R, Rashid Asif
Department of Pathology, The University of Texas M D Anderson Cancer Center, Houston 77030, USA.
Oncogene. 2003 Feb 13;22(6):924-34. doi: 10.1038/sj.onc.1206123.
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.
类癌肿瘤和胰腺内分泌肿瘤（PETs）是罕见的神经内分泌肿瘤，其基因改变尚未得到充分表征。CpG岛甲基化是一种基因沉默机制，并且在肿瘤中已描述了多个CpG岛的一致性甲基化，即CpG岛甲基化表型（CIMP）。本研究的目的是评估类癌肿瘤和PETs中的CIMP。我们研究了16例类癌肿瘤、11例PETs以及22例相关的正常黏膜或胰腺。通过甲基化特异性PCR（MSP）或联合亚硫酸氢盐限制性分析（COBRA）评估了p14、p16、环氧化酶2（COX2）、O（6）-甲基鸟嘌呤甲基转移酶（MGMT）、雌激素受体（ER）、血小板反应蛋白1（THBS1）、视黄酸受体β2（RARβ）、T型钙通道（CACNA1G）和多发性内分泌肿瘤1型（MEN1）基因以及MINT1、MINT2、MINT25、MINT27和MINT31位点的甲基化状态。类癌肿瘤中RARβ、MGMT、p16、COX2、p14、THBS1和ER的甲基化频率较高，范围为肿瘤的25%至63%。其他CpG岛很少甲基化或未甲基化。相邻的正常黏膜中ER、COX2和RARβ也发生甲基化，但p14、p16、THBS1和MGMT的甲基化是肿瘤特异性的。相比之下，PETs和正常胰腺仅在ER处经常发生甲基化。在MGMT（25%对0%，p = 0.03）、THBS1（44%对9%，p = 0.04）、p14（44%对9%，p = 0.04）和RARβ（25%对0%，p = 0.03）方面，类癌肿瘤中的甲基化比PETs更频繁。类癌肿瘤中p16蛋白表达的缺失与p16基因的甲基化相关（p = 0.006）。我们的研究表明，类癌肿瘤的甲基化谱与PETs不同，反映了不同的分子发病机制。
