Somatic <it>VHL </it>gene alterations in MEN2-associated medullary thyroid carcinoma
<p>Abstract</p> <p>Background</p> <p>Germline mutations in <it>RET </it>are responsible for multiple endocrine neoplasia type 2 (MEN2), an autosomal dominantly inherited cancer syndrome that is characterized by medullary thyroid carcinoma (MTC), pheochromocy...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2006-05-01
|
| Series: | BMC Cancer |
| Online Access: | http://www.biomedcentral.com/1471-2407/6/131 |
| _version_ | 1811250207923372032 |
|---|---|
| author | Pacak Karel Zhuang Zhengping Libutti Steven K Tannapfel Andrea Vortmeyer Alexander O Brouwers Frederieke M Koch Christian A Neumann Hartmut PH Paschke Ralf |
| author_facet | Pacak Karel Zhuang Zhengping Libutti Steven K Tannapfel Andrea Vortmeyer Alexander O Brouwers Frederieke M Koch Christian A Neumann Hartmut PH Paschke Ralf |
| author_sort | Pacak Karel |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Germline mutations in <it>RET </it>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 <it>RET</it>. Somatic <it>VHL </it>gene alterations are implicated in the pathogenesis of MEN2 pheochromocytomas. We hypothesized that somatic <it>VHL </it>gene alterations are also important in the pathogenesis of MEN2-associated MTC.</p> <p>Methods</p> <p>We analyzed 6 MTCs and 1 C-cell hyperplasia (CCH) specimen from 7 patients with MEN2A and <it>RET </it>germline mutations in codons 609, 618, 620, or 634, using microdissection, microsatellite analysis, phosphorimage densitometry, and <it>VHL </it>mutation analysis.</p> <p>Results</p> <p>First, we searched for allelic imbalance between mutant and wild-type <it>RET </it>by using the polymorphic markers D10S677, D10S1239, and RET on thyroid tissue from these patients. Evidence for <it>RET </it>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 <it>VHL </it>gene locus at 3p25/26. <it>VHL </it>gene deletion was present in 3 MTCs. These 3 MTCs also had an allelic imbalance between mutant and wild-type <it>RET</it>. 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 <it>RET </it>and somatic <it>VHL </it>gene deletion, no somatic <it>VHL </it>mutation could be detected. The CCH specimen did neither reveal <it>RET </it>imbalance nor somatic <it>VHL </it>gene alterations.</p> <p>Conclusion</p> <p>These data suggest that a <it>RET </it>germline mutation is necessary for development of CCH, that allelic imbalance between mutant and wild-type <it>RET </it>may set off tumorigenesis, and that somatic <it>VHL </it>gene alterations may not play a major role in tumorigenesis of MEN2A-associated MTC.</p> |
| first_indexed | 2024-04-12T16:01:00Z |
| format | Article |
| id | doaj.art-f7e160ce9e6c49bd8a6dc59dff64d7d1 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-04-12T16:01:00Z |
| publishDate | 2006-05-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-f7e160ce9e6c49bd8a6dc59dff64d7d12022-12-22T03:26:13ZengBMCBMC Cancer1471-24072006-05-016113110.1186/1471-2407-6-131Somatic <it>VHL </it>gene alterations in MEN2-associated medullary thyroid carcinomaPacak KarelZhuang ZhengpingLibutti Steven KTannapfel AndreaVortmeyer Alexander OBrouwers Frederieke MKoch Christian ANeumann Hartmut PHPaschke Ralf<p>Abstract</p> <p>Background</p> <p>Germline mutations in <it>RET </it>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 <it>RET</it>. Somatic <it>VHL </it>gene alterations are implicated in the pathogenesis of MEN2 pheochromocytomas. We hypothesized that somatic <it>VHL </it>gene alterations are also important in the pathogenesis of MEN2-associated MTC.</p> <p>Methods</p> <p>We analyzed 6 MTCs and 1 C-cell hyperplasia (CCH) specimen from 7 patients with MEN2A and <it>RET </it>germline mutations in codons 609, 618, 620, or 634, using microdissection, microsatellite analysis, phosphorimage densitometry, and <it>VHL </it>mutation analysis.</p> <p>Results</p> <p>First, we searched for allelic imbalance between mutant and wild-type <it>RET </it>by using the polymorphic markers D10S677, D10S1239, and RET on thyroid tissue from these patients. Evidence for <it>RET </it>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 <it>VHL </it>gene locus at 3p25/26. <it>VHL </it>gene deletion was present in 3 MTCs. These 3 MTCs also had an allelic imbalance between mutant and wild-type <it>RET</it>. 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 <it>RET </it>and somatic <it>VHL </it>gene deletion, no somatic <it>VHL </it>mutation could be detected. The CCH specimen did neither reveal <it>RET </it>imbalance nor somatic <it>VHL </it>gene alterations.</p> <p>Conclusion</p> <p>These data suggest that a <it>RET </it>germline mutation is necessary for development of CCH, that allelic imbalance between mutant and wild-type <it>RET </it>may set off tumorigenesis, and that somatic <it>VHL </it>gene alterations may not play a major role in tumorigenesis of MEN2A-associated MTC.</p>http://www.biomedcentral.com/1471-2407/6/131 |
| spellingShingle | Pacak Karel Zhuang Zhengping Libutti Steven K Tannapfel Andrea Vortmeyer Alexander O Brouwers Frederieke M Koch Christian A Neumann Hartmut PH Paschke Ralf Somatic <it>VHL </it>gene alterations in MEN2-associated medullary thyroid carcinoma BMC Cancer |
| title | Somatic <it>VHL </it>gene alterations in MEN2-associated medullary thyroid carcinoma |
| title_full | Somatic <it>VHL </it>gene alterations in MEN2-associated medullary thyroid carcinoma |
| title_fullStr | Somatic <it>VHL </it>gene alterations in MEN2-associated medullary thyroid carcinoma |
| title_full_unstemmed | Somatic <it>VHL </it>gene alterations in MEN2-associated medullary thyroid carcinoma |
| title_short | Somatic <it>VHL </it>gene alterations in MEN2-associated medullary thyroid carcinoma |
| title_sort | somatic it vhl it gene alterations in men2 associated medullary thyroid carcinoma |
| url | http://www.biomedcentral.com/1471-2407/6/131 |
| work_keys_str_mv | AT pacakkarel somaticitvhlitgenealterationsinmen2associatedmedullarythyroidcarcinoma AT zhuangzhengping somaticitvhlitgenealterationsinmen2associatedmedullarythyroidcarcinoma AT libuttistevenk somaticitvhlitgenealterationsinmen2associatedmedullarythyroidcarcinoma AT tannapfelandrea somaticitvhlitgenealterationsinmen2associatedmedullarythyroidcarcinoma AT vortmeyeralexandero somaticitvhlitgenealterationsinmen2associatedmedullarythyroidcarcinoma AT brouwersfrederiekem somaticitvhlitgenealterationsinmen2associatedmedullarythyroidcarcinoma AT kochchristiana somaticitvhlitgenealterationsinmen2associatedmedullarythyroidcarcinoma AT neumannhartmutph somaticitvhlitgenealterationsinmen2associatedmedullarythyroidcarcinoma AT paschkeralf somaticitvhlitgenealterationsinmen2associatedmedullarythyroidcarcinoma |