Molecular Genetic Studies of Sporadic and MEN1-Associated Endocrine Pancreatic Tumors

• Pancreatic endocrine tumors (PETs) may cause typical syndromes of hormone excess, or appear clinically non-functioning without hormonal symptoms. PETs occur sporadically, in association with the multiple endocrine neoplasia type 1 (MEN1) syndrome, or rarely the von Hippel-Lindau syndrome. Molecular genetic investigations may reveal pathways important for tumor development, and be of clinical use.The aim of this thesis was to investigate regulation of different genes involved in cell proliferation, and relate findings to signs of malignancy in PETs.The MEN1 gene on chromosome 11q13 was mutated in three out of eleven sporadic malignant PETs. Two nonsense mutations, causing truncation of the protein, and one missense mutation were found.Relation of allelic loss at 11q13 and 3p25 to malignant behavior was observed in sporadic PETs. Allelic loss at 18q21 was found in a subset of sporadic and MEN1-associated PETs, and mutation analysis of Smad4 excluded a tumor suppressor gene function.In PETs with allelic loss on chromosome 3p25, mutation analysis of WNT7A and HDAC11 excluded function as tumor suppressor genes.Menin, encoded by the MEN1 gene, was reported to regulate expression of the cyclin-dependent kinase inhibitors CDKN2C/p18, CDKN1B/p27, and CDKN2B/p15 in mouse pancreatic islet tumor models. Here, the mRNA expression of these genes was not related to MEN1 gene mutations in human PETs.Cyclin-dependent kinase 4 (CDK4) and the protooncogene c-Myc were found to be overexpressed regardless of MEN1 gene mutational status of the PETs. The CDK4 gene was neither amplified nor mutated. Targeting of CDK4 may present an alternative to traditional chemotherapy of PETs in the future.

Keyword

Surgery

pancreatic endocrine tumor

MEN1

LOH

WNT7A

HDAC11

CDK4

CDKN2B/p15

CDKN1B/p27

CDKN2C/p18

c-Myc

Smad4

pyrosequencing

epigenetic

methylation

tumor suppressor

Kirurgi

Publication and Content Type

vet (subject category)

dok (subject category)