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CpG island methylation in carcinoid and pancreatic endocrine tumors
Annie On-On Chan1, Sang Geol Kim, Ahmed Bedeir
1Department of Pathology, The University of Texas M D Anderson Cancer Center, Houston 77030, USA.
Abstract:
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.
Insights
CpG island methylation patterns differ between carcinoid tumors and pancreatic endocrine tumors (PETs), indicating distinct molecular origins. This study highlights key gene methylation differences in these rare neuroendocrine neoplasms.
Area of Science:
- Neuroendocrine Neoplasms
- Cancer Genomics
- Epigenetics
Background:
- Carcinoid tumors and pancreatic endocrine tumors (PETs) are rare neuroendocrine neoplasms with poorly understood genetic alterations.
- CpG island methylation is a gene silencing mechanism, and the CpG island methylator phenotype (CIMP) is observed in various tumors.
Purpose of the Study:
- To investigate the CpG island methylation status in carcinoid tumors and PETs.
- To compare the methylation profiles of carcinoid tumors and PETs to understand their distinct molecular pathogenesis.
Main Methods:
- Methylation-specific PCR (MSP) and combined bisulfite restriction analysis (COBRA) were used to assess methylation status.
- Analyzed methylation of specific genes (p14, p16, COX2, MGMT, ER, THBS1, RARbeta, CACNA1G, MEN1) and MINT loci in 16 carcinoid tumors, 11 PETs, and matched normal tissues.
Main Results:
- Carcinoid tumors frequently showed methylation at RARbeta, MGMT, p16, COX2, p14, THBS1, and ER (25-63%).
- PETs and normal pancreas primarily showed ER methylation; normal mucosa also had ER, COX2, and RARbeta methylation.
- Carcinoid tumors exhibited significantly higher methylation frequencies than PETs for MGMT, THBS1, p14, and RARbeta. Loss of p16 protein expression correlated with p16 gene methylation in carcinoid tumors.
Conclusions:
- The distinct methylation profiles of carcinoid tumors and PETs suggest different underlying molecular pathogenesis.
- Epigenetic alterations, specifically gene methylation, play a role in the development of these neuroendocrine tumors.