Low Frequency of <i>p16^INK4a</i> Alterations in Insulinomas

Abstract

Background/Aims: The molecular mechanisms contributing to the tumorigenesis of insulinomas are poorly understood. Disruption of the cell cycle due to inactivation of the p16^INK4a tumor-suppressor gene was identified in a variety of human tumors, including gastrinomas and nonfunctioning endocrine pancreatic carcinomas. In this study the role of p16^INK4a in the tumorigenesis of insulinomas was evaluated. Methods: Seventeen insulinomas (14 benign, 3 malignant) were analyzed for genetic alterations in the p16^INK4a tumor-suppressor gene by SSCP, PCR-based deletion and methylation-specific assays. p16 expression was determined by immunohistochemistry. Results: One malignant insulinoma showed a homozygous deletion of p16^INK4a and another two benign insulinomas revealed aberrant methylation of the p16^INK4a promoter region. All three tumors lacked p16 expression according to immunohistochemistry. None of the insulinomas carried intragenic p16^INK4a mutations. In total, 17% of insulinomas had p16^INK4a alterations. Conclusions: The p16^INK4a tumor-suppressor gene contributes to tumorigenesis in only a small subset of insulinomas.

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

“…CDKN2A gene mutations and methylation of the promoter region in PETs and WDNTs have been reported (Bartsch et al, 2000;Lubomierski et al, 2001;Chan et al, 2003). We have previously reported that WDNTs of the gastrointestinal tract lack CDKN2A gene mutation, but the gene is silenced by methylation and chromosomal deletion (Chan et al, 2003).…”

Allelic alterations in pancreatic endocrine tumors identified by genome-wide single nucleotide polymorphism analysis

“…The molecular mechanisms of tumor genesis of PETs are poorly understood but have been the focus of many recent reports (Görtz et al 1999, Bartsch et al 2000, Serrano et al 2000, Lubomierski et al 2001, Chan et al 2003, House et al 2003. Previous studies using comparative genomic hybridization and microsatellite allelotyping have shown that PETs have a high frequency of chromosomal allelic alterations that are located on chromosomes 3q, 6q, 11q, 11p, 16p, 20q, 21, and 22q (Chung et al 1998, Rigaud et al 2001).…”

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.…”