Aberrant Hypermethylation of Tumor Suppressor Genes in Pancreatic Endocrine Neoplasms

House, Michael G.; Herman, James G.; Guo, Ming; Hooker, Craig M.; Schulick, Richard D.; Lillemoe, Keith D.; Cameron, John L.; Hruban, Ralph H.; Maitra, Anirban; Yeo, Charles J.

doi:10.1097/01.sla.0000086659.49569.9e

Cited by 159 publications

(154 citation statements)

References 30 publications

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“…Previous studies have shown that carcinoid tumors or pancreatic endocrine tumors lack KRAS mutations, 5,19 but have methylation of RASSF1A gene in pancreatic endocrine tumors 49 and lung carcinoid tumors. 50 Our study demonstrated that alcohol consumption was more common in carcinoid tumors and compared to pancreatic endocrine tumors, and ileal carcinoid tumors had frequent loss of the entire chromosome 18.…”

Section: Discussionmentioning

confidence: 99%

Comparison of genetic alterations in neuroendocrine tumors: frequent loss of chromosome 18 in ileal carcinoid tumors

et al. 2005

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Carcinoid tumors and pancreatic endocrine tumors are uncommon neuroendocrine neoplasms, and their genetic alterations are not well characterized. These tumors have site-specific differences in neuroendocrine characteristics, clinical course and genetic alterations. We compared clinicopathological features and loss of heterozygosity of chromosomes 11q, 16q and 18, and BRAF gene mutations in 47 patients with neuroendocrine tumors including 16 with pancreatic endocrine tumors, 15 with nonileal carcinoid tumors and 16 with ileal carcinoid tumors. Patients with carcinoid tumors had more frequent history of alcohol consumption compared to patients with pancreatic endocrine tumors (P ¼ 0.02), and patients with ileal carcinoid tumors more frequently had liver metastasis compared to patients with nonileal carcinoid tumors and pancreatic endocrine tumors (P ¼ 0.02). Allelic loss of chromosome 11q was present in 21% of tumors, chromosome 16q in 13%, and chromosome 18 in 30%. These alterations differed with the anatomical subsite of tumor: allelic loss of chromosome 18 was present in 69% of ileal carcinoid tumors, 13% of nonileal carcinoid tumors and 6% of pancreatic endocrine tumors (P ¼ 0.001). In contrast to pancreatic endocrine tumors and nonileal carcinoid tumors, all 11 ileal tumors with loss of chromosome 18 had complete loss of both chromosomal arms. No BRAF mutations were identified. Complete allelic loss of chromosome 18 was associated with smaller tumor size (P ¼ 0.02). Our study indicates that genetic alterations vary by tumor subsite and clinicopathologic features, and ileal carcinoid tumors have distinctive clinicopathologic and genetic profiles.

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Section: Discussionmentioning

confidence: 99%

Comparison of genetic alterations in neuroendocrine tumors: frequent loss of chromosome 18 in ileal carcinoid tumors

et al. 2005

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“…CIMP phenotype defined as 2 or more genes methylated was found in 80% of the tumours (Arnold et al 2007). CDKN2a (p16) promoter is methylated in 40% of PanNET, and it is associated with early tumour recurrence and reduced overall survival (House et al 2003). Hypermethylation of the promoter of TIMP-3 (tissue inhibitor of metalloproteinase-3) gene was found in 44% of PanNET in a study performed on 18 PanNET in correlation with protein loss.…”

Section: Pancreatic Netmentioning

confidence: 99%

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Domenico

Wiedmer

Perren

2017

Endocrine-Related Cancer

102

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Neuroendocrine tumours (NET) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumours. The molecular characterization and the clinical classification of these tumours have been evolving slowly and show differences according to organs of origin. Novel technologies such as next-generation sequencing revealed new molecular aspects of NET over the last years. Notably, whole-exome/genome sequencing (WES/WGS) approaches underlined the very low mutation rate of well-differentiated NET of all organs compared to other malignancies, while the engagement of epigenetic changes in driving NET evolution is emerging. Indeed, mutations in genes encoding for proteins directly involved in chromatin remodelling, such as DAXX and ATRX are a frequent event in NET. Epigenetic changes are reversible and targetable; therefore, an attractive target for treatment. The discovery of the mechanisms underlying the epigenetic changes and the implication on gene and miRNA expression in the different subgroups of NET may represent a crucial change in the diagnosis of this disease, reveal new therapy targets and identify predictive markers. Molecular profiles derived from omics data including DNA mutation, methylation, gene and miRNA expression have already shown promising results in distinguishing clinically and molecularly different subtypes of NET. In this review, we recapitulate the major genetic and epigenetic characteristics of pancreatic, lung and small intestinal NET and the affected pathways. We also discuss potential epigenetic mechanisms leading to NET development.

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“…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.…”

mentioning

confidence: 99%

“…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.…”

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confidence: 99%

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

et al. 2007

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Neuroendocrine tumors including carcinoid tumors and pancreatic endocrine tumors are uncommon, and the genetic alterations in these indolent tumors are not well characterized. We studied global hypomethylation by analyzing long interspersed nucleotide elements (LINE)-1 and Alu methylation using pyrosequencing in 35 neuroendocrine tumors and corresponding normal tissue. The tumor samples were less methylated than normal tissue at LINE-1 (P ¼ 0.04) and Alu (P ¼ 0.001). The mean relative tumor hypomethylation (difference in methylation between normal tissue and in tumor) was 11.5710.0 for LINE-1 and 5.876.4 for Alu, and were correlated with each other (correlation coefficient 0.6, P ¼ 0.001). Relative tumor hypomethylation of LINE-1 was higher in ileal carcinoid tumors than in non-ileal carcinoid tumors and pancreatic endocrine tumors (P ¼ 0.047), and tumors with lymph node metastasis (P ¼ 0.02), chromosome 18 loss (P ¼ 0.001) and RAS-association domain family 1, isoform A gene methylation (P ¼ 0.02). Alu methylation in tumors was inversely correlated with methylation of O 6 -methyl-guanine methyltransferase gene (P ¼ 0.02). Our study shows that hypomethylation is more common in carcinoid tumors than in pancreatic endocrine tumors and is associated with clinicopathologic features, and genetic and epigenetic alterations in these tumors, including lymph node metastasis.

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Aberrant Hypermethylation of Tumor Suppressor Genes in Pancreatic Endocrine Neoplasms

Abstract: Aberrant methylation of multiple tumor suppressor genes is associated with advanced tumor stage and identifies molecularly distinct PENs with identical histologic characteristics. The methylation status of specific tumor suppressor genes is predictive of PEN behavior.

Cited by 159 publications

References 30 publications

Comparison of genetic alterations in neuroendocrine tumors: frequent loss of chromosome 18 in ileal carcinoid tumors

Comparison of genetic alterations in neuroendocrine tumors: frequent loss of chromosome 18 in ileal carcinoid tumors

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

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

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