CpG island methylation in carcinoid and pancreatic endocrine tumors

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, cyclooxygenase 2 (COX2), O 6 -methyl-guanine methyltransferase (MGMT), estrogen receptor (ER), thrombospondin 1 (THBS1), retinoic acid receptor beta 2 (RARb), 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 RARb, 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 RARb, 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 ¼ 0.03), THBS1 (44 versus 9%, P ¼ 0.04), p14 (44 versus 9%, P ¼ 0.04) and RARb (25 versus 0%, P ¼ 0.03). Loss of p16 protein expression correlated with methylation of p16 gene in carcinoid tumors (P ¼ 0.006). Our study indicates that methylation profile of carcinoid tumors differs from PETs, reflecting different molecular pathogenesis.

High-resolution genomic profiling reveals gain of chromosome 14 as a predictor of poor outcome in ileal carcinoids

“…Our knowledge about the genetic and epigenetic alterations that lead to ileal carcinoid formation is limited and pathogenetic mechanisms have not yet been identified. Several genes have been studied, but no mutations have been identified in TP53, KRAS, CTNNB1, CDKN2A, SMAD2, SMAD4 and BRAF (Weckström et al 1996, Younes et al 1997, Löllgen et al 2001, Chan et al 2003, Wang et al 2005, Kulke et al 2008. However, epigenetic changes such as genome-wide hypomethylation of LINE-1 and Alu-repetitive sequences and promoter hypermethylation of specific genes, i.e.…”

“…However, epigenetic changes such as genome-wide hypomethylation of LINE-1 and Alu-repetitive sequences and promoter hypermethylation of specific genes, i.e. RASSF1A, CTNNB1, LAMB3, CDKN2A, CDH1, LAMC2 and THBS1, have been reported in a subset of tumours (Chan et al 2003, Liu et al 2005, Zhang et al 2006, Choi et al 2007.…”

Hypomethylation of LINE-1 and Alu in well-differentiated neuroendocrine tumors (pancreatic endocrine tumors and carcinoid tumors)

“…1,2 The molecular mechanisms of neuroendocrine tumors are poorly understood but have been the focus of many recent reports. [3][4][5][6][7][8][9][10] The methylation of cytosine in CpG dinucleotides is an important epigenetic modification of DNA in the vertebrate genome. 11 Methylation of cytosines and other associated epigenetic modifications is associated with transcriptional silencing of about one-half of the human genes with abundant CpG dinucleotides (CpG islands) in the promoter region, and is important in development and aging.…”

“…Some tumors produce endocrine activity causing a clinical syndrome, variable growth patterns and behavior and involvement of multiple endocrine neoplasia type 1 gene, but have site-specific differences in other genetic and epigenetic alterations. [3][4][5][6][7][8][9][10] We studied methylation of LINE-1 and Alu in low-grade neuroendocrine tumors and corresponding normal tissue from the same patients, and compared methylation densities of tumor, normal tissue and relative tumor hypomethylation (difference in methylation between normal and tumor) with clinicopathologic features.…”

Allelic alterations in well‐differentiated neuroendocrine tumors (carcinoid tumors) identified by genome‐wide single nucleotide polymorphism analysis and comparison with pancreatic endocrine tumors

“…The molecular mechanisms of WDNTs genesis are poorly understood but have been the focus of many recent reviews (Leotlela et al, 2003;Ö berg, 2005;Zikusoka et al, 2005) and reports of genetic and epigenetic alterations (Serrano et al, 2000;Lubomierski et al, 2001;Chan et al, 2003;Karnik et al, 2005;Wang et al, 2005;Yokoyama et al, 2005;Choi et al, 2007). There are site-specific differences among WDNTs from lung and various subsites of gastrointestinal tract, including clinicopathological features, behavior, and prognosis.…”