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

Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (J.S., S.U.G., P.L.P., F.G., R.T.J.), and Laboratory of Pathology, National Cancer Institute (I.A.L.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Robert T. Jensen, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9C-103, 10 Center Drive, MSC 1804, Bethesda, Maryland 20892-1804. E-mail: robertj{at}bdg10.niddk.nih.gov

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 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 p16^INK4a 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 p16^INK4a 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 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 (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 p16^INK4a 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 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 because it is independent of the primary gastrinoma location, which is now thought to have different origins, methylation of the p16^INK4a gene is probably a central process in the molecular pathogenesis of these tumors.

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