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Somatic VHL gene alterations in MEN2-associated medullary thyroid carcinoma.

Koch CA, Brouwers FM, Vortmeyer AO, Tannapfel A, Libutti SK, Zhuang Z, Pacak K, Neumann HP, Paschke R - BMC Cancer (2006)

Bottom Line: Recent studies suggest a "second hit" mechanism resulting in amplification of mutant RET.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.These 3 MTCs also had an allelic imbalance between mutant and wild-type RET.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Endocrinology and Nephrology, University of Leipzig, Philipp-Rosenthalstr, 27, 04103 Leipzig, Germany. ckoch@medicine.umsmed.edu

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.

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LOH analysis of the VHL gene locus of 3 cases of MEN 2A-related MTCs with marker D3S1038 or D3S1110. All cases show loss of one allele in microdissected tumor tissue (T), whereas heterozygosity is retained in normal non-neoplastic tissue (N). Arrows indicate the 2 VHL alleles.
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Figure 2: LOH analysis of the VHL gene locus of 3 cases of MEN 2A-related MTCs with marker D3S1038 or D3S1110. All cases show loss of one allele in microdissected tumor tissue (T), whereas heterozygosity is retained in normal non-neoplastic tissue (N). Arrows indicate the 2 VHL alleles.

Mentions: We studied 6 medullary thyroid carcinomas and 1 C-cell hyperplasia specimen from 7 patients with MEN 2A and known RET germline mutations for allelic imbalance at the RET locus and for somatic genetic alterations at the VHL gene locus at 3p25/26 including LOH and mutations (Table 1). Allelic imbalance between the mutant and wild-type RET allele could be demonstrated in 3 MTCs (Fig. 1). The same 3 tumors also had LOH of the VHL gene locus (Fig. 2).


Somatic VHL gene alterations in MEN2-associated medullary thyroid carcinoma.

Koch CA, Brouwers FM, Vortmeyer AO, Tannapfel A, Libutti SK, Zhuang Z, Pacak K, Neumann HP, Paschke R - BMC Cancer (2006)

LOH analysis of the VHL gene locus of 3 cases of MEN 2A-related MTCs with marker D3S1038 or D3S1110. All cases show loss of one allele in microdissected tumor tissue (T), whereas heterozygosity is retained in normal non-neoplastic tissue (N). Arrows indicate the 2 VHL alleles.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1483898&req=5

Figure 2: LOH analysis of the VHL gene locus of 3 cases of MEN 2A-related MTCs with marker D3S1038 or D3S1110. All cases show loss of one allele in microdissected tumor tissue (T), whereas heterozygosity is retained in normal non-neoplastic tissue (N). Arrows indicate the 2 VHL alleles.
Mentions: We studied 6 medullary thyroid carcinomas and 1 C-cell hyperplasia specimen from 7 patients with MEN 2A and known RET germline mutations for allelic imbalance at the RET locus and for somatic genetic alterations at the VHL gene locus at 3p25/26 including LOH and mutations (Table 1). Allelic imbalance between the mutant and wild-type RET allele could be demonstrated in 3 MTCs (Fig. 1). The same 3 tumors also had LOH of the VHL gene locus (Fig. 2).

Bottom Line: Recent studies suggest a "second hit" mechanism resulting in amplification of mutant RET.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.These 3 MTCs also had an allelic imbalance between mutant and wild-type RET.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Endocrinology and Nephrology, University of Leipzig, Philipp-Rosenthalstr, 27, 04103 Leipzig, Germany. ckoch@medicine.umsmed.edu

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.

Show MeSH
Related in: MedlinePlus