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Alterations in the p16INK4a/CDKN2A tumor suppressor gene in gastrinomas
J Serrano1, S U Goebel, P L Peghini
1Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1804, USA.
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.
Insights
Methylation of the p16INK4a gene is common in gastrinomas, occurring early in tumor development. This gene alteration does not predict tumor behavior or prognosis in neuroendocrine tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The p16INK4a/CDKN2A gene (p16INK4a) is frequently altered in various nonendocrine tumors, potentially predicting tumor behavior.
- The role of p16INK4a alterations in neuroendocrine tumors, specifically gastrinomas, remains unclear.
Purpose of the Study:
- To investigate p16INK4a gene alterations (mutations, deletions, methylation) in gastrinomas.
- To correlate these alterations with the biological behavior, growth patterns, and aggressiveness of gastrinomas.
Main Methods:
- Analysis of p16INK4a gene in gastrinomas from 44 patients for mutations, polymorphisms, and homozygous deletions.
- Assessment of 5'-CpG island promoter hypermethylation of the p16INK4a gene.
- Longitudinal clinical assessment including imaging studies and radionuclide scanning for tumor behavior and growth patterns.
Main Results:
- No mutations or homozygous deletions of the p16INK4a gene were found in gastrinomas.
- Polymorphisms in the p16INK4a gene were observed in 54% of cases.
- Hypermethylation of the p16INK4a gene promoter occurred in 52% of gastrinomas.
- p16INK4a methylation did not correlate with clinical characteristics, biological behavior, prognostic factors, or postresection growth patterns.
Conclusions:
- Methylation of the p16INK4a gene is the most frequent alteration identified in gastrinomas to date.
- p16INK4a methylation is likely an early event in gastrinoma pathogenesis, independent of disease stage.
- p16INK4a methylation is probably a central process in the molecular pathogenesis of gastrinomas, irrespective of primary tumor location.
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