Sub theme 3.1.5
Endocrine Tumors

Goals of research: general outline
Scientific achievements
Future plans: special goals and approach
Running projects
Associated staff

Goals of research: general outline

Pheochromocytomas are catecholamine-producing tumours of the adrenal glands. Paragangliomas are their non-adrenal counterparts that may or may not (head and neck area) produce hormones. These tumours are the focus of research in the Erasmus MC since more than 10 years in a collaboration between the departments of Pathology, Internal Medicine, Surgery and more recently also the departments of Clinical Genetics and Otorhinolaryngology. The main interest is concentrated on the pathogenesis of these tumours, which is still largely unknown, aiming at the distinction of more aggressive tumours as opposed to more indolent tumours, which form the large majority. Also, the hereditary nature is actively investigated, as now almost one third of patients have been shown to carry germline mutations.

Scientific achievements

For the elucidation of the pathogenesis of PCC and PGL, genome-wide approaches have been employed, which have confirmed the importance of several chromosomal losses (1p, 3p, 3q, 11p, 21q and 22q). Moreover, it has been shown that there does not appear to be one region of common overlap on 1p, so that the presence of a single tumor suppressor gene on this chromosomal arm is questionable. Interestingly, there appear to be two groups of PCC, each with their own specific loss profile, either 1p/3q losses or 3p/11p losses. The former group corresponds to hereditary PCC with RET mutations, whereas the latter group is akin to hereditary PCC with VHL/SDH mutations.

A very useful additional tool in the study of PCC is the development of a mouse model for malignant PCC by the group of Prof. Jan Trapman. A conditional PTEN knock-out mouse shows PCC at high frequency (78%), which metastasize to the lungs. This is one of very few mouse models that have malignant PCC and probably the only that develops spontaneously at this frequency.

The field of hereditary PCC and PGL has moved tremendously over the past period of time, starting with the description of SDHB, SDHC and SDHD as the genes for the PGL4, PGL3 and PGL1 loci, respectively, in 2000/2001. Since then, we and others have shown that these genes are collectively responsible (together with RET, VHL and NF1) for almost one third of PCC and PGL cases. Somatic mutations in the SDH genes are rare, but do occur. Now that 6 candidate genes are known, the issue of genetic testing becomes relevant. We have shown that a simple and robust immunohistochemical assay for SDHB protein yields a high specificity (84%) and sensitivity (100%) for the detection or exclusion of SDH gene mutations in PCC or PGL.

Future plans: special goals and approach

Our genome-wide approach will be carried on describing the DNA based losses and gains in a group of malignant PCC. Experiments have been performed and analysis is under way. The preliminary data show that it might be achievable to pinpoint a limited set of genomic abnormalities that allows the distinction of benign from malignant PCC. Furthermore, gene expression profiling experiments have been done, which are currently analyzed. Again, a distinction between benign and malignant PCC, based on a limited gene set, is expected. These data will be further validated on an independent set of tumours and the results will be compared with those from the group of Prof. Anne-Paule Gimenez-Roqueplo in Paris, with whom collaboration has been set up in the past year. It is expected that this will lead to further confirmatory studies, as well as to give indications for pathogenetic mechanisms involved in PCC tumorigenesis.

New mouse models (PTEN/p53 double knock-out mice) by the group of Prof. Jan Trapman have shown an even higher frequency of PCC and malignancy and will be further studied and compared with the orginal mouse strains. An international consortium has been set up to execute a clinical trial for malignant PCC in humans. This mouse model will be an important addition to this study to investigate the effect of new drugs in the treatment of PCC.

The results of our SDHB immunohistochemical study need further confirmation in a large independent cohort for which a larger national and international collaboration will be set up with the Universities of Leiden and Nijmegen, as well as with Prof. Hartmut Neumann from the University of Freiburg. In addition, a new susceptibility gene, SDH5, now renamed as SDHAF2, for PGL has been described most recently. This is the gene located in the PGL2 locus, which causes familial PGL. So far, it appears that this gene does not play a major role in apparently sporadic PCC and PGL. Future work will be directed at the elucidation of the SDH pathway in PGL tumorigenesis. Also, the occurrence of additional tumours in the PCC-PGL syndrome will be the subject of further work.

Most recent publications

1.      van Nederveen FH, Gaal J, Favier J, Korpershoek E, Oldenburg RA, de Bruyn EM, Sleddens HF, Derkx P, Rivière J, Dannenberg H, Petri BJ, Komminoth P, Pacak K, Hop WC, Pollard PJ, Mannelli M, Bayley JP, Perren A, Niemann S, Verhofstad AA, de Bruïne AP, Maher ER, Tissier F, Méatchi T, Badoual C, Bertherat J, Amar L, Alataki D, Van Marck E, Ferrau F, François J, de Herder WW, Peeters MP, van Linge A, Lenders JW, Gimenez-Roqueplo AP, de Krijger RR, Dinjens WN. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol. 2009 Aug;10(8):764-71. Epub 2009 Jul 1. PubMed PMID: 19576851.

2.      van Nederveen FH, Korpershoek E, deLeeuw RJ, Verhofstad AA, Lenders JW, Dinjens WN, Lam WL, de Krijger RR. Array-comparative genomic hybridization in sporadic benign pheochromocytomas. Endocr Relat Cancer. 2009 Jun;16(2):505-13. Epub 2009 Jan 19. PubMed PMID: 19153209.

3.      Korpershoek E, Loonen AJ, Corvers S, van Nederveen FH, Jonkers J, Ma X, Ziel-van der Made A, Korsten H, Trapman J, Dinjens WN, de Krijger RR. Conditional Pten knock-out mice: a model for metastatic phaeochromocytoma. J Pathol. 2009 Mar;217(4):597-604. PubMed PMID: 19142977.

4.      Petri BJ, Speel EJ, Korpershoek E, Claessen SM, van Nederveen FH, Giesen V, Dannenberg H, van der Harst E, Dinjens WN, de Krijger RR. Frequent loss of 17p, but no p53 mutations or protein overexpression in benign and malignant pheochromocytomas. Mod Pathol. 2008 Apr;21(4):407-13. Epub 2008 Jan 25. PubMed PMID: 18223555.

5.      Korpershoek E, Petri BJ, van Nederveen FH, Dinjens WN, Verhofstad AA, de Herder WW, Schmid S, Perren A, Komminoth P, de Krijger RR. Candidate gene mutation analysis in bilateral adrenal pheochromocytoma and sympathetic paraganglioma. Endocr Relat Cancer. 2007 Jun;14(2):453-62. PubMed PMID: 17639058.

6.      van Nederveen FH, Korpershoek E, Lenders JW, de Krijger RR, Dinjens WN. Somatic SDHB mutation in an extraadrenal pheochromocytoma. N Engl J Med. 2007 Jul 19;357(3):306-8. PubMed PMID: 17634472.

7.      Dannenberg H, van Nederveen FH, Abbou M, Verhofstad AA, Komminoth P, de Krijger RR, Dinjens WN. Clinical characteristics of pheochromocytoma patients with germline mutations in SDHD. J Clin Oncol. 2005 Mar 20;23(9):1894-901. PubMed PMID: 15774781.

8.      Aarts M, Dannenberg H, deLeeuw RJ, van Nederveen FH, Verhofstad AA, Lenders JW, Dinjens WN, Speel EJ, Lam WL, de Krijger RR. Microarray-based CGH of sporadic and syndrome-related pheochromocytomas using a 0.1-0.2 Mb bacterial artificial chromosome array spanning chromosome arm 1p. Genes Chromosomes Cancer. 2006 Jan;45(1):83-93. PubMed PMID: 16215979.

9.      van Nederveen FH, Perren A, Dannenberg H, Petri BJ, Dinjens WN, Komminoth P, de Krijger RR. PTEN gene loss, but not mutation, in benign and malignant phaeochromocytomas. J Pathol. 2006 Jun;209(2):274-80. PubMed PMID: 16538614.

10.  Korpershoek E, Van Nederveen FH, Dannenberg H, Petri BJ, Komminoth P, Perren A, Lenders JW, Verhofstad AA, De Herder WW, De Krijger RR, Dinjens WN. Genetic analyses of apparently sporadic pheochromocytomas: the Rotterdam experience. Ann  N Y Acad Sci. 2006 Aug;1073:138-48. PubMed PMID: 17102080.