HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Accepted manuscript (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Schmitt, A. Articles by Perren, A. PubMed PubMed Citation Articles by Schmitt, A. Articles by Perren, A.

A Schmitt, Department of Pathology, Institute of Surgical Pathology, Zürich, 8091, Switzerland
S Schmid, Department of Pathology, Institute of Surgical Pathology, Zurich, Switzerland
T Rudolph, Department of Pathology, Institute of Surgical Pathology, Zurich, Switzerland
M Anlauf, University of Kiel, Institute of Pathology, Kiel, Germany
C Prinz, Klinikum rechts der Isar, Technische Universitaet Muenchen, Department of Gastroenterology, Munich, Germany
G Klöppel, University of Kiel, Institute of Pathology, Kiel, Germany
H Moch, Department of Pathology, Institute of Surgical Pathology, Zurich, Switzerland
P Heitz, Department of Pathology, Institute of Surgical Pathology, Zurich, Switzerland
P Komminoth, City Hospital Triemli, Department of Pathology, Zurich, Switzerland
A Perren, Department of Pathology, Institute of Pathology, Bern, Switzerland

Correspondence: Anja Schmitt, Email: anja.schmitt{at}pathology.unibe.ch

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 harbour 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 PET examined. In 2 of 35 informative PET (6%) methylation of the VHL promoter region was detected and VHL deletion by FISH was found in 14 of 79 PET (18%). HIF1-, CA-9 and GLUT-1 protein was expressed in 19%, 27% and 30% of the 152 PET examined. Protein expression of the HIF-1 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- (p < 0.005) and GLUT-1 immunohistochemistry (p < 0.001). These PET with VHL alterations and signs of hypoxia signalling where 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 an 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.