Alterations in the p16^INK4a/CDKN2A Tumor Suppressor Gene in Gastrinomas

Abstract

The p16INK4a/CDKN2A gene (p16INK4a) is frequently altered by homozygous deletion, mutation, or methylation in many nonendocrine tumors, and these alterations may be predictive of recurrence, tumor growth, or aggressiveness. Whether this is true of neuroendocrine tumors such as gastrinomas is unclear. To address this question we analyzed the gastrinomas from 44 patients for p16INK4a gene mutations and correlated the results to the tumor's biological behavior, growth pattern, and aggressiveness. No gastrinomas had mutations of exon 1 or exon 2 of the p16INK4a gene, although polymorphisms were found in 54%. No homozygous deletions were found. In 52% of the gastrinomas, hypermethylation of a 5'-CpG island of the p16INK4a gene promoter was found. To assess the growth behavior of the gastrinomas, all patients were assessed yearly with at least three conventional imaging studies (computed tomography scan, magnetic resonance imaging, and ultrasound), and since 1994 have been assessed with radionuclide scanning using [111In-diethylenetriamine pentaacetic acid,DPhe1]octreotide. The mean follow-up was 5.1+/-0.4 yr (range, 1.2-11.7). The presence or absence of methylation of the p16INK4a gene did not correlate with clinical characteristics of the gastrinoma, biological behavior (gastrin release and basal or maximal acid output), the presence or absence of known prognostic factors (tumor size, gastrinoma location, lymph node metastases, liver metastases, and curability), or growth pattern of the gastrinoma postresection. These results indicate that methylation of the p16INK4a gene is the most common gene alteration described to date in gastrinomas. Furthermore, because it is independent of disease stage it is probably an early event in the pathogenesis and because it is independent of the primary gastrinoma location, which is now thought to have different origins, methylation of the p16INK4a gene is probably a central process in the molecular pathogenesis of these tumors.

The diversity and commonalities of gastroenteropancreatic neuroendocrine tumors

“…Hypermethylation (with subsequent gene silencing) of the promoter region of p16 INK4A occurs in~50% of gastrinomas [80]; the relevance of this is unknown. Some investigators have suggested that HER-2/neu amplification, over expression of epidermal growth factor (EGF), and hepatocyte growth factor (HGF) may be associated with an aggressive growth phenotype [76,81,82].…”

CpG island methylation in carcinoid and pancreatic endocrine tumors

“…Homozygous deletion and methylation of p16 gene are present in PETs (Weber and Jensen, 1996;Serrano et al, 2000). Other genetic alterations, including alterations of K-ras and p53 genes that are commonly present in other epithelial malignancies of the gastrointestinal tract, are infrequent in carcinoid tumors or PETs (Weber and Jensen, 1996;Rindi et al, 1999a).…”

Epigenetic alterations in endocrine-related cancer

“…The tumor suppressor gene P16, a cell cycle regulator, is frequently methylated in other tumors such as ovarian tumor (Abou-Zeid et al 2011, Bammidi et al 2012) and this promoter methylation was also observed in 52% of gastrinomas in a study by Serrano et al (2000) as an early event, independent of the stage or localization of the disease. However, only limited studies have been conducted in relation to the role of epigenetic mechanisms in other endocrine pancreatic tumors (Table 1).…”