Somatic VHL gene alterations in MEN2-associated medullary thyroid carcinoma

Christian A. Koch, Frederieke M. Brouwers, Alexander O. Vortmeyer, Andrea Tannapfel, Steven K. Libutti, Zhengping Zhuang, Karel Pacak, Hartmut P H Neumann, Ralf Paschke

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Abstract

Background: Germline mutations in RET are responsible for multiple endocrine neoplasia type 2 (MEN2), an autosomal dominantly inherited cancer syndrome that is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia/adenoma. Recent studies suggest a "second hit" mechanism resulting in amplification of mutant RET. Somatic VHL gene alterations are implicated in the pathogenesis of MEN2 pheochromocytomas. We hypothesized that somatic VHL gene alterations are also important in the pathogenesis of MEN2-associated MTC. Methods: We analyzed 6 MTCs and 1 C-cell hyperplasia (CCH) specimen from 7 patients with MEN2A and RET germline mutations in codons 609, 618, 620, or 634, using microdissection, microsatellite analysis, phosphorimage densitometry, and VHL mutation analysis. Results: First, we searched for allelic imbalance between mutant and wild-type RET by using the polymorphic markers D10S677, D10S1239, and RET on thyroid tissue from these patients. Evidence for RET amplification by this technique could be demonstrated in 3 of 6 MTCs. We then performed LOH analysis using D3S1038 and D3S1110 which map to the VHL gene locus at 3p25/26. VHL gene deletion was present in 3 MTCs. These 3 MTCs also had an allelic imbalance between mutant and wild-type RET. Mutation analysis of the VHL gene showed a somatic frameshift mutation in 1 MTC that also demonstrated LOH at 3p25/26. In the 2 other MTCs with allelic imbalance of RET and somatic VHL gene deletion, no somatic VHL mutation could be detected. The CCH specimen did neither reveal RET imbalance nor somatic VHL gene alterations. Conclusion: These data suggest that a RET germline mutation is necessary for development of CCH, that allelic imbalance between mutant and wild-type RET may set off tumorigenesis, and that somatic VHL gene alterations may not play a major role in tumorigenesis of MEN2A-associated MTC.

Original languageEnglish (US)
Article number131
JournalBMC Cancer
Volume6
DOIs
StatePublished - May 17 2006
Externally publishedYes

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Multiple Endocrine Neoplasia Type 2a
Allelic Imbalance
Hyperplasia
Germ-Line Mutation
Genes
Gene Deletion
Pheochromocytoma
Mutation
Carcinogenesis
Microdissection
Parathyroid Neoplasms
Frameshift Mutation
Densitometry
Codon
Microsatellite Repeats
Medullary Thyroid cancer
Thyroid Gland
3-(methylthio)catechol
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Koch, C. A., Brouwers, F. M., Vortmeyer, A. O., Tannapfel, A., Libutti, S. K., Zhuang, Z., ... Paschke, R. (2006). Somatic VHL gene alterations in MEN2-associated medullary thyroid carcinoma. BMC Cancer, 6, [131]. https://doi.org/10.1186/1471-2407-6-131

Somatic VHL gene alterations in MEN2-associated medullary thyroid carcinoma. / Koch, Christian A.; Brouwers, Frederieke M.; Vortmeyer, Alexander O.; Tannapfel, Andrea; Libutti, Steven K.; Zhuang, Zhengping; Pacak, Karel; Neumann, Hartmut P H; Paschke, Ralf.

In: BMC Cancer, Vol. 6, 131, 17.05.2006.

Research output: Contribution to journalArticle

Koch, CA, Brouwers, FM, Vortmeyer, AO, Tannapfel, A, Libutti, SK, Zhuang, Z, Pacak, K, Neumann, HPH & Paschke, R 2006, 'Somatic VHL gene alterations in MEN2-associated medullary thyroid carcinoma', BMC Cancer, vol. 6, 131. https://doi.org/10.1186/1471-2407-6-131
Koch CA, Brouwers FM, Vortmeyer AO, Tannapfel A, Libutti SK, Zhuang Z et al. Somatic VHL gene alterations in MEN2-associated medullary thyroid carcinoma. BMC Cancer. 2006 May 17;6. 131. https://doi.org/10.1186/1471-2407-6-131
Koch, Christian A. ; Brouwers, Frederieke M. ; Vortmeyer, Alexander O. ; Tannapfel, Andrea ; Libutti, Steven K. ; Zhuang, Zhengping ; Pacak, Karel ; Neumann, Hartmut P H ; Paschke, Ralf. / Somatic VHL gene alterations in MEN2-associated medullary thyroid carcinoma. In: BMC Cancer. 2006 ; Vol. 6.
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AU - Brouwers, Frederieke M.

AU - Vortmeyer, Alexander O.

AU - Tannapfel, Andrea

AU - Libutti, Steven K.

AU - Zhuang, Zhengping

AU - Pacak, Karel

AU - Neumann, Hartmut P H

AU - Paschke, Ralf

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N2 - Background: Germline mutations in RET are responsible for multiple endocrine neoplasia type 2 (MEN2), an autosomal dominantly inherited cancer syndrome that is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia/adenoma. Recent studies suggest a "second hit" mechanism resulting in amplification of mutant RET. Somatic VHL gene alterations are implicated in the pathogenesis of MEN2 pheochromocytomas. We hypothesized that somatic VHL gene alterations are also important in the pathogenesis of MEN2-associated MTC. Methods: We analyzed 6 MTCs and 1 C-cell hyperplasia (CCH) specimen from 7 patients with MEN2A and RET germline mutations in codons 609, 618, 620, or 634, using microdissection, microsatellite analysis, phosphorimage densitometry, and VHL mutation analysis. Results: First, we searched for allelic imbalance between mutant and wild-type RET by using the polymorphic markers D10S677, D10S1239, and RET on thyroid tissue from these patients. Evidence for RET amplification by this technique could be demonstrated in 3 of 6 MTCs. We then performed LOH analysis using D3S1038 and D3S1110 which map to the VHL gene locus at 3p25/26. VHL gene deletion was present in 3 MTCs. These 3 MTCs also had an allelic imbalance between mutant and wild-type RET. Mutation analysis of the VHL gene showed a somatic frameshift mutation in 1 MTC that also demonstrated LOH at 3p25/26. In the 2 other MTCs with allelic imbalance of RET and somatic VHL gene deletion, no somatic VHL mutation could be detected. The CCH specimen did neither reveal RET imbalance nor somatic VHL gene alterations. Conclusion: These data suggest that a RET germline mutation is necessary for development of CCH, that allelic imbalance between mutant and wild-type RET may set off tumorigenesis, and that somatic VHL gene alterations may not play a major role in tumorigenesis of MEN2A-associated MTC.

AB - Background: Germline mutations in RET are responsible for multiple endocrine neoplasia type 2 (MEN2), an autosomal dominantly inherited cancer syndrome that is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia/adenoma. Recent studies suggest a "second hit" mechanism resulting in amplification of mutant RET. Somatic VHL gene alterations are implicated in the pathogenesis of MEN2 pheochromocytomas. We hypothesized that somatic VHL gene alterations are also important in the pathogenesis of MEN2-associated MTC. Methods: We analyzed 6 MTCs and 1 C-cell hyperplasia (CCH) specimen from 7 patients with MEN2A and RET germline mutations in codons 609, 618, 620, or 634, using microdissection, microsatellite analysis, phosphorimage densitometry, and VHL mutation analysis. Results: First, we searched for allelic imbalance between mutant and wild-type RET by using the polymorphic markers D10S677, D10S1239, and RET on thyroid tissue from these patients. Evidence for RET amplification by this technique could be demonstrated in 3 of 6 MTCs. We then performed LOH analysis using D3S1038 and D3S1110 which map to the VHL gene locus at 3p25/26. VHL gene deletion was present in 3 MTCs. These 3 MTCs also had an allelic imbalance between mutant and wild-type RET. Mutation analysis of the VHL gene showed a somatic frameshift mutation in 1 MTC that also demonstrated LOH at 3p25/26. In the 2 other MTCs with allelic imbalance of RET and somatic VHL gene deletion, no somatic VHL mutation could be detected. The CCH specimen did neither reveal RET imbalance nor somatic VHL gene alterations. Conclusion: These data suggest that a RET germline mutation is necessary for development of CCH, that allelic imbalance between mutant and wild-type RET may set off tumorigenesis, and that somatic VHL gene alterations may not play a major role in tumorigenesis of MEN2A-associated MTC.

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