Alterations in the p16(INK4a)/CDKN2A tumor suppressor gene in gastrinomas

The p16(INK4a)/CDKN2A gene (p16(INK4a)) is frequently altered by homozygous deletion, mutation, or methylation in many nonendocrine tumors, and these alterations may be predictive of recurrence, tumor growth, or aggressivenes s. Whether this is true of neuroendocrine tumors such as gastrinomas is unc lear. To address this question we analyzed the gastrinomas from 44 patients for p16(INK4a) gene mutations and correlated the results to the tumor's bi ological behavior, growth pattern, and aggressiveness. No gastrinomas had m utations of exon 1 or exon 2 of the p16(INK4a) gene, although polymorphisms were found in 54%. No homozygous deletions were found. In 52% of the gastr inomas, hypermethylation of a 5'-CpG island of the p16(INK4a) gene promoter was found. To assess the growth behavior of the gastrinomas, all patients were assessed yearly with at least three conventional imaging studies (comp uted tomography scan, magnetic resonance imaging, and ultrasound), and sinc e 1994 have been assessed with radionuclide scanning using [In-111-diethyle netriamine pentaacetic acid,DPhe(1)] octreotide. The mean follow-up was 5.1 +/- 0.4 yr (range, 1.2-11.7). The presence or absence of methylation of th e p16(INK4a) gene did not correlate with clinical characteristics of the ga strinoma, biological behavior (gastrin release and basal or maximal acid ou tput), the presence or absence of known prognostic factors (tumor size, gas trinoma location, lymph node metastases, liver metastases, and curability), or growth pattern of the gastrinoma postresection. These results indicate that methylation of the p16(INK4a) 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 becaus e it is independent of the primary gastrinoma location, which is now though t to have different origins, methylation of the p16(INK4a) gene is probably a central process in the molecular pathogenesis of these tumors.