Background/Aims: The molecular mechanisms contributing to the tumorigenesis of insulinomas are poorly understood. Disruption of the cell cycle due to inactivation of the p16INK4a tumor-suppressor gene was identified in a variety of human tumors, including gastrinomas and nonfunctioning endocrine pancreatic carcinomas. In this study the role of p16INK4a in the tumorigenesis of insulinomas was evaluated. Methods: Seventeen insulinomas (14 benign, 3 malignant) were analyzed for genetic alterations in the p16INK4a 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 p16INK4a and another two benign insulinomas revealed aberrant methylation of the p16INK4a promoter region. All three tumors lacked p16 expression according to immunohistochemistry. None of the insulinomas carried intragenic p16INK4a mutations. In total, 17% of insulinomas had p16INK4aalterations. Conclusions: The p16INK4a tumor-suppressor gene contributes to tumorigenesis in only a small subset of insulinomas.

Journal Section:
Original Paper: Endocrine Tumors
Keywords:
Insulinoma, p16INK4a tumor-suppressor gene
1.
Klöppel G, Höfler H, Heintz PU: Pancreatic endocrine tumors in man; in Polak JM (ed): Endocrine Pancreas. Edinburgh, Churchill Livingstone, 1993, pp 91–121.
2.
Edis AJ, Grant CS, Egdahl RH:1984 Manual of Endocrine Surgery. Heidelberg, Springer, 1984.
3.
Zhuang Z, Vortmeyer AO, Pack S, Huang S, Pham TA, Wang C, Park W-S, Agarwal SK, Debelenko LV, Kester MB, Guru SC, Manickam P, Olufemi SE, Yu F, Heppner C, Crabtree JS, Skarulis MC, Venzon DJ, Emmert-Buck MR, Spiegel AM, Chandrasekharappa SC, Collins FS, Burns AL, Marx SJ, Jensen RT, Liotta LA, Lubensky IA: Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas. Cancer Res 1997;57:4682–4686.
[PubMed]
4.
Yashiro T, Fulton N, Hara H, Yasuda K, Montag A, Yashiro N, Srauss F, Ito K, Aisyoshi Y, Kaplan EL: Comparison of mutations of ras oncogene in human pancreatic exocrine and endocrine tumors. Surgery 1993;114:758–764.
[PubMed]
5.
Yoshimoto K, Iwahana H, Fukuda A, Sano T, Katsuragi M, Saito S, Itakura M: Role of p53 mutations in endocrine tumorigenesis: Mutation detection by polymerase chain reaction-single strand polymorphism. Cancer Res 1992;53:1057–1062.
6.
Pavelic K, Hrascan R, Kapitanovic S, Vranes Z, Belicza M, Kruslin B, Cabrijan T: Molecular genetics of malignant insulinoma. Anticancer Res 1996;16:1707–1717.
[PubMed]
7.
Bartsch D, Hahn SA, Danichevski K, Ramaswamy A, Bastian D, Galehdari H, Barth P, Schmiegel W, Simon B, Rothmund M: Mutations of the DPC4/Smad4 gene in neuroendocrine pancreatic tumors. Oncogene 1999;18:2367–2371.
[PubMed]
8.
Bartsch D, Shevlin DW, Tung WS, Kisker O, Wells SA Jr, Goodfellow PJ: Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas. Genes Chromosom Cancer 1995;14:189–195.
[PubMed]
9.
Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK, Moskaluk CA, Hahn SA, Schwarte-Waldhoff I, Schmiegel W, Baylin SB, Kern SE, Herman JG: Abrogation of the Rb/p16 tumor-supressive pathway in virtually all pancreatic carcinomas. Cancer Res 1997;57:3126–3130.
[PubMed]
10.
Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CL, Kern SE: Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinomas. Nature Genet 1994;8:27–32.
[PubMed]
https://doi.org/10.1038/ng0994-27
11.
Muscarella P, Melvin S, Fisher WE, Foor J, Ellison C, Herman, Schirmer WJ, Hitchcock CL, DeYoung BR, Weghorst CM: Genetic alterations in gastrinoma and nonfunctioning pancreatic neuroendocrine tumors: An analysis of p16/MTS1 tumor suppressor gene inactivation. Cancer Res 1998;58:237–240.
[PubMed]
12.
Bartsch D, Kersting M, Schilling T, Ramaswamy A, Gerdes B, Bastian D, Schuermann M, Rothmund M: p16INK4a alterations in gastrinomas and non-functioning islet cell carcinomas. Langenbecks Arch Chir (Forumband 99), 13–16.
13.
Gorden P, Skarulis MC, Roach P, Comi RJ, Fraker DL, Norton JA, Alexander HR, Doppman JL: Plasma proinsulin-like component in insulinoma: A 25-year experience. J Clin Endocrinol Metab 1995;80:2884–2887.
[PubMed]
14.
Hussussian CJ, Struewing JP, Goldstein AM, Higgins PAT, Ally DS, Sheahan MD, Clark WH, Tucker MA, Dracopoli NC: Germline p16 mutations in familial melanoma. Nature Genet 1994;8:15–21.
[PubMed]
15.
Naumann M, Savitskaia, Eilert C, Schramm A, Kalthoff H, Schmiegel W: Frequent codeletion of p16/MTS1 and p15/MTS2 and genetic alterations in p16/MTS1 in pancreatic tumors. Gastroenterology 1996;110:1215–1224.
[PubMed]
16.
Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB: Methylation-specific PCR: A novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 1996;93:9821–9826.
[PubMed]
https://doi.org/10.1073/pnas.93.18.9821
17.
Wilentz RE, Geradts J, Maynard R, Offerhaus GJA, Kang M, Goggins M, Yeo CJ, Kern SE, Hruban RH: Inactivation of the p16 (INK4a) tumor suppressor gene in pancreatic duct lesions: Loss of intranuclear expression. Cancer Res 1998;58:4740–4744.
[PubMed]
18.
Maynard R, Hruban RH, Schutte M, Kern SE, Geradts J: Immunohistochemical reactivity of mutant p16 proteins in paraffin sections: A comparison of four antibodies. Mod Pathol 1998;11:19a.
19.
Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA: Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 1994;368:753–756.
[PubMed]
https://doi.org/10.1038/368753a0
20.
Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS, Johnson BE, Skolnick MH: A cell cycle regulator potentially involved in genesis of many tumor types. Science 1994;264:436–440.
[PubMed]
21.
Reed AL, Califano J, Cairns P, Westra WH, Jones RM, Koch W, Ahrendt S, Eby Y, Sewell D, Nawroz H, Bartek J, Sidransky D: High frequency of p16 (CDKN2/MTS1/INK4a) inactivation in head and neck squamous cell carcinomas. Cancer Res 1996;56:3630–3633.
[PubMed]
22.
Gonzalez-Zulueta M, Bender CM, Yang AS, Nguyen T, Beart RW, Van Tornout JM, Jones PA: Methylation of the 5′ CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissue correlates with gene silencing. Cancer Res 1995;55:4531–4535.
[PubMed]
23.
Cairns P, Mao L, Merlo A, Lee DJ, Schwab D, Eby Y, Tokino K, van der Riet P, Blaugrund JE, Sidransky D: Rates of p16 (MTS1) mutations in primary tumors with 9p loss. Science 1994;265:415–417.
[PubMed]
24.
Chung DC, Smith AP, Louis DN, Graeme-Cook F, Warshaw AL, Arnold A: Analysis of the retinoblastoma tumour suppressor gene in pancreatic endocrine tumours. Clin Endocrinol 1997;47:523–528.
© 2000 S. Karger AG, Basel
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