Quick Search:

uzh logo
Browse by:
bullet
bullet
bullet
bullet

Zurich Open Repository and Archive 

Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-27437

Schmitt, A M; Schmid, S; Rudolph, T; Anlauf, M; Prinz, C; Klöppel, G; Moch, H; Heitz, P U; Komminoth, P; Perren, A (2009). VHL inactivation is an important pathway for the development of malignant sporadic pancreatic endocrine tumors. Endocrine-Related Cancer, 16(4):1219-1227.

[img]
Preview
PDF
1MB

Abstract

A small subset of familial pancreatic endocrine tumors (PET) arises in patients with von Hippel-Lindau syndrome and these tumors may have an adverse outcome compared to other familial PET. Sporadic PET rarely harbors somatic VHL mutations, but the chromosomal location of the VHL gene is frequently deleted in sporadic PET. A subset of sporadic PET shows active hypoxia signals on mRNA and protein level. To identify the frequency of functionally relevant VHL inactivation in sporadic PET and to examine a possible prognostic significance we correlated epigenetic and genetic VHL alterations with hypoxia signals. VHL mutations were absent in all 37 PETs examined. In 2 out of 35 informative PET (6%) methylation of the VHL promoter region was detected and VHL deletion by fluorescence in situ hybridization was found in 14 out of 79 PET (18%). Hypoxia inducible factor 1alpha (HIF1-alpha), carbonic anhydrase 9 (CA-9), and glucose transporter 1 (GLUT-1) protein was expressed in 19, 27, and 30% of the 152 PETs examined. Protein expression of the HIF1-alpha downstream target CA-9 correlated significantly with the expression of CA-9 RNA (P<0.001), VHL RNA (P<0.05), and VHL deletion (P<0.001) as well as with HIF1-alpha (P<0.005) and GLUT-1 immunohistochemistry (P<0.001). These PET with VHL alterations and signs of hypoxia signalling were characterized by a significantly shortened disease-free survival. We conclude that VHL gene impairment by promoter methylation and VHL deletion in nearly 25% of PET leads to the activation of the HIF-pathway. Our data suggest that VHL inactivation and consecutive hypoxia signals may be a mechanism for the development of sporadic PET with an adverse outcome.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Surgical Pathology
DDC:610 Medicine & health
Language:English
Date:2009
Deposited On:31 Jan 2010 10:49
Last Modified:28 Nov 2013 01:02
Publisher:Society for Endocrinology
ISSN:1351-0088
Publisher DOI:10.1677/ERC-08-0297
PubMed ID:19690016
Citations:Web of Science®. Times Cited: 21
Google Scholar™
Scopus®. Citation Count: 20

Users (please log in): suggest update or correction for this item

Repository Staff Only: item control page