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Somatic VHL gene deletion and point mutation in MEN 2A-associated pheochromocytoma

Oncogene volume 21, pages 479–482 (2002)Cite this article

Abstract

Multiple endocrine neoplasia type 2 (MEN 2) is an inherited cancer syndrome that includes pheochromocytoma. Germline mutations in RET are responsible for MEN 2 but the precise pathogenetic mechanisms of tumorigenesis are unknown. We have recently identified possible mechanisms of tumor formation in patients with MEN 2A-related pheochromocytoma. Two of nine tumors investigated, however, did not reveal either of these mechanisms. In the present study, we therefore searched for other possible mechanisms underlying the pathogenesis of MEN 2A-related pheochromocytoma. Hereditary pheochromocytoma also occurs in patients with von Hippel-Lindau (VHL) disease, a syndrome consisting of tumors caused by inactivation of the VHL tumor suppressor gene. A subset of sporadic pheochromocytomas have somatic mutations in RET or VHL, suggesting that both genes contribute to pheochromocytoma pathogenesis in a subset of tumors. It is unknown, however, whether VHL gene alterations would be associated with tumorigenesis in hereditary, MEN 2-related pheochromocytoma. We therefore investigated four pheochromocytomas from patients with MEN 2A and RET germline mutations for the presence of allelic deletion and/or somatic mutation of the VHL gene. LOH analysis using the polymorphic markers D3S1038 and D3S1110 that map to the VHL gene locus 3p25/26, revealed evidence for somatic VHL gene deletion in all four MEN 2A-related pheochromocytomas. Mutation analysis of the VHL gene showed frameshift mutations in two tumors and a splice acceptor mutation in one tumor. The remaining tumor did show LOH but not mutation of the VHL gene. These results suggest that somatic genetic alterations of the VHL gene may play a role in the tumorigenesis of some MEN 2A-related pheochromocytomas.

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Acknowledgements

We thank Dr Nieman, Clinical Director, NIH, NICHD, for support of this study.

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Author notes

  1. Christian A Koch and Steve C Huang: These two authors contributed equally to this study

Authors and Affiliations

  1. Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Disease (NICHD), National Institutes of Health (NIH), Bethesda, 20892, Maryland, MD, USA

    Christian A Koch, George P Chrousos & Karel Pacak

  2. Molecular Pathogenesis Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, 20892, Maryland, MD, USA

    Steve C Huang, Zhengping Zhuang & Alexander O Vortmeyer

  3. Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Catherine Stolle

  4. Georgetown University, Washington, DC, USA

    Norio Azumi, Alexander O Vortmeyer & Karel Pacak

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  1. Christian A Koch
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  2. Steve C Huang
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  3. Zhengping Zhuang
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  4. Catherine Stolle
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  5. Norio Azumi
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Correspondence to Christian A Koch.

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Koch, C., Huang, S., Zhuang, Z. et al. Somatic VHL gene deletion and point mutation in MEN 2A-associated pheochromocytoma. Oncogene 21, 479–482 (2002). https://doi.org/10.1038/sj.onc.1205133

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