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Molecular genetics of malignant insulinoma.
Anticancer Res 1996 Jul-Aug; 16(4A):1707-17AR

Abstract

Malignant insulinoma is an rare form of cancer with poor prognosis and a reported 5-year survival of 35%. Relatively little is known about the etiology of this disease or of the oncogenes and tumor suppressor genes that participate in its genesis and progression. To address this issue, several protooncogenes, including K-ras, N-ras, erbB-2, erbB-3,c-myc, c-fos, c-jun were examined. Also analyzed was the expression of the growth factors TGF-alpha, EGF, and insulin as well as the EGF receptor (EGF-R), p53 and the putative anti-metastasis gene nm23-H1. These were examined in malignant insulinomas, benign insulinomas, pancreatic B cell hyperplasias and in normal endocrine pancreas. Normal endocrine pancreas showed moderate immunoreaction for c-myc and a strong reaction for insulin. All other parameters were negative. Benign pancreatic B cell hyperplasias were slightly or moderately positive for N-ras and TGF-alpha, and were weakly positive for EGF-R. They were strongly positive for c-myc and insulin. In malignant insulinomas there was strong immunoreaction for c-myc, TGF-alpha, N-ras, K-ras and p53. Insulin reaction was moderate or strong. Molecular genetic studies have been performed for the presence of activating point mutations in codon 12 of the c-K-ras oncogene. Mutations were detected using primer-mediated, mutant-enriched, polymerase chain reaction-restriction fragment length polymorphism analysis and were further characterized by allele-specific oligonucleotide hybridization. Four out of six patients with malignant insulinoma and two out of eight patients with benign insulinoma harbored K-ras point mutations at codon 12. All patients with mutated K-ras oncogene also had elevated levels of p53 protein as well as c-myc and TGF-alpha. In one extremely malignant case we found concomitant mutation at codon 12 of K-ras and codon 61 of the N-ras gene. Our data are consistent with the idea that malignant progression is accompanied by the progressive accumulation of multiple genetic lesions and suggest that activation of myc, TGF-alpha and ras genes may be early events in the development of insulinoma.

Authors+Show Affiliations

Department of Molecular Medicine, Ruder Boskovic Institute, Zagreb, Croatia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

8712689

Citation

Pavelic, K, et al. "Molecular Genetics of Malignant Insulinoma." Anticancer Research, vol. 16, no. 4A, 1996, pp. 1707-17.
Pavelic K, Hrascan R, Kapitanovic S, et al. Molecular genetics of malignant insulinoma. Anticancer Res. 1996;16(4A):1707-17.
Pavelic, K., Hrascan, R., Kapitanovic, S., Vranes, Z., Cabrijan, T., Spaventi, S., ... Pavelic, Z. P. (1996). Molecular genetics of malignant insulinoma. Anticancer Research, 16(4A), pp. 1707-17.
Pavelic K, et al. Molecular Genetics of Malignant Insulinoma. Anticancer Res. 1996;16(4A):1707-17. PubMed PMID: 8712689.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular genetics of malignant insulinoma. AU - Pavelic,K, AU - Hrascan,R, AU - Kapitanovic,S, AU - Vranes,Z, AU - Cabrijan,T, AU - Spaventi,S, AU - Korsic,M, AU - Krizanac,S, AU - Li,Y Q, AU - Stambrook,P, AU - Gluckman,J L, AU - Pavelic,Z P, PY - 1996/7/1/pubmed PY - 1996/7/1/medline PY - 1996/7/1/entrez SP - 1707 EP - 17 JF - Anticancer research JO - Anticancer Res. VL - 16 IS - 4A N2 - Malignant insulinoma is an rare form of cancer with poor prognosis and a reported 5-year survival of 35%. Relatively little is known about the etiology of this disease or of the oncogenes and tumor suppressor genes that participate in its genesis and progression. To address this issue, several protooncogenes, including K-ras, N-ras, erbB-2, erbB-3,c-myc, c-fos, c-jun were examined. Also analyzed was the expression of the growth factors TGF-alpha, EGF, and insulin as well as the EGF receptor (EGF-R), p53 and the putative anti-metastasis gene nm23-H1. These were examined in malignant insulinomas, benign insulinomas, pancreatic B cell hyperplasias and in normal endocrine pancreas. Normal endocrine pancreas showed moderate immunoreaction for c-myc and a strong reaction for insulin. All other parameters were negative. Benign pancreatic B cell hyperplasias were slightly or moderately positive for N-ras and TGF-alpha, and were weakly positive for EGF-R. They were strongly positive for c-myc and insulin. In malignant insulinomas there was strong immunoreaction for c-myc, TGF-alpha, N-ras, K-ras and p53. Insulin reaction was moderate or strong. Molecular genetic studies have been performed for the presence of activating point mutations in codon 12 of the c-K-ras oncogene. Mutations were detected using primer-mediated, mutant-enriched, polymerase chain reaction-restriction fragment length polymorphism analysis and were further characterized by allele-specific oligonucleotide hybridization. Four out of six patients with malignant insulinoma and two out of eight patients with benign insulinoma harbored K-ras point mutations at codon 12. All patients with mutated K-ras oncogene also had elevated levels of p53 protein as well as c-myc and TGF-alpha. In one extremely malignant case we found concomitant mutation at codon 12 of K-ras and codon 61 of the N-ras gene. Our data are consistent with the idea that malignant progression is accompanied by the progressive accumulation of multiple genetic lesions and suggest that activation of myc, TGF-alpha and ras genes may be early events in the development of insulinoma. SN - 0250-7005 UR - https://www.unboundmedicine.com/medline/citation/8712689/Molecular_genetics_of_malignant_insulinoma_ L2 - http://www.diseaseinfosearch.org/result/3837 DB - PRIME DP - Unbound Medicine ER -