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Somatic VHL gene deletion and point mutation in MEN 2A-associated pheochromocytoma
Christian A Koch1, Steve C Huang, Zhengping Zhuang
1Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Disease (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, MD 20892, USA. kochc@exchange.nih.gov
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.
Insights
Somatic VHL gene alterations, including deletions and mutations, are implicated in the development of pheochromocytoma in patients with Multiple Endocrine Neoplasia type 2A (MEN 2A), suggesting a role beyond RET mutations in this inherited cancer syndrome.
Area of Science:
- Oncology
- Genetics
- Endocrinology
Background:
- Multiple Endocrine Neoplasia type 2 (MEN 2) is an inherited cancer syndrome characterized by pheochromocytoma, with germline RET mutations being the known cause.
- The exact mechanisms driving tumorigenesis in MEN 2-related pheochromocytoma remain unclear, necessitating further investigation beyond RET mutations.
- Von Hippel-Lindau (VHL) disease, caused by VHL gene inactivation, also leads to hereditary pheochromocytoma, and somatic mutations in VHL have been observed in sporadic pheochromocytomas.
Purpose of the Study:
- To investigate the potential role of VHL gene alterations in the pathogenesis of MEN 2A-related pheochromocytoma.
- To determine if allelic deletion or somatic mutation of the VHL gene occurs in pheochromocytomas from MEN 2A patients with known germline RET mutations.
Main Methods:
- Analysis of four pheochromocytomas from MEN 2A patients with germline RET mutations.
- Loss of heterozygosity (LOH) analysis at the VHL gene locus (3p25/26) using polymorphic markers D3S1038 and D3S1110.
- Mutation analysis of the VHL gene in the selected tumors.
Main Results:
- Somatic VHL gene deletion (Loss of Heterozygosity) was detected in all four MEN 2A-related pheochromocytomas analyzed.
- VHL gene mutations, including frameshift and splice acceptor mutations, were identified in three of the four tumors.
- One tumor exhibited VHL gene deletion but no detectable mutation, suggesting potential alternative VHL inactivation mechanisms.
Conclusions:
- Somatic genetic alterations of the VHL gene appear to contribute to the tumorigenesis of a subset of MEN 2A-related pheochromocytomas.
- These findings expand the understanding of pheochromocytoma pathogenesis in MEN 2A, highlighting the involvement of the VHL tumor suppressor gene.
- Further research is warranted to elucidate the precise mechanisms by which VHL alterations contribute to MEN 2A-associated pheochromocytoma development.