Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression
<p>Abstract</p> <p>Background</p> <p>Germline mutations in the <it>folliculin </it>(<it>FLCN</it>) gene are associated with the development of Birt-Hogg-Dubé syndrome (BHDS), a disease characterized by papular skin lesions, a high occurrence of s...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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BMC
2010-12-01
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| Series: | BMC Medical Genomics |
| Online Access: | http://www.biomedcentral.com/1755-8794/3/59 |
| _version_ | 1818917473041252352 |
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| author | Yonneau Laurent Méjean Arnaud Denoux Yves Giraud Sophie Gad Sophie Nordenskjöld Magnus Bergerheim Ulf Aly Markus Zickert Peter Sääf Annika Yang Ximing J Chen Jindong Dykema Karl J Niemi Natalie M Petillo David Klomp Jeff A Vasiliu Viorel Richard Stéphane MacKeigan Jeffrey P Teh Bin T Furge Kyle A |
| author_facet | Yonneau Laurent Méjean Arnaud Denoux Yves Giraud Sophie Gad Sophie Nordenskjöld Magnus Bergerheim Ulf Aly Markus Zickert Peter Sääf Annika Yang Ximing J Chen Jindong Dykema Karl J Niemi Natalie M Petillo David Klomp Jeff A Vasiliu Viorel Richard Stéphane MacKeigan Jeffrey P Teh Bin T Furge Kyle A |
| author_sort | Yonneau Laurent |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Germline mutations in the <it>folliculin </it>(<it>FLCN</it>) gene are associated with the development of Birt-Hogg-Dubé syndrome (BHDS), a disease characterized by papular skin lesions, a high occurrence of spontaneous pneumothorax, and the development of renal neoplasias. The majority of renal tumors that arise in BHDS-affected individuals are histologically similar to sporadic chromophobe renal cell carcinoma (RCC) and sporadic renal oncocytoma. However, most sporadic tumors lack <it>FLCN </it>mutations and the extent to which the BHDS-derived renal tumors share genetic defects associated with the sporadic tumors has not been well studied.</p> <p>Methods</p> <p>BHDS individuals were identified symptomatically and <it>FLCN </it>mutations were confirmed by DNA sequencing. Comparative gene expression profiling analyses were carried out on renal tumors isolated from individuals afflicted with BHDS and a panel of sporadic renal tumors of different subtypes using discriminate and clustering approaches. qRT-PCR was used to confirm selected results of the gene expression analyses. We further analyzed differentially expressed genes using gene set enrichment analysis and pathway analysis approaches. Pathway analysis results were confirmed by generation of independent pathway signatures and application to additional datasets.</p> <p>Results</p> <p>Renal tumors isolated from individuals with BHDS showed distinct gene expression and cytogenetic characteristics from sporadic renal oncocytoma and chromophobe RCC. The most prominent molecular feature of BHDS-derived kidney tumors was high expression of mitochondria-and oxidative phosphorylation (OXPHOS)-associated genes. This mitochondria expression phenotype was associated with deregulation of the PGC-1α-TFAM signaling axis. Loss of <it>FLCN </it>expression across various tumor types is also associated with increased nuclear mitochondrial gene expression.</p> <p>Conclusions</p> <p>Our results support a genetic distinction between BHDS-associated tumors and other renal neoplasias. In addition, deregulation of the PGC-1α-TFAM signaling axis is most pronounced in renal tumors that harbor <it>FLCN </it>mutations and in tumors from other organs that have relatively low expression of <it>FLCN</it>. These results are consistent with the recently discovered interaction between FLCN and AMPK and support a model in which FLCN is a regulator of mitochondrial function.</p> |
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| institution | Directory Open Access Journal |
| issn | 1755-8794 |
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| last_indexed | 2024-12-20T00:34:37Z |
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| spelling | doaj.art-219aa39d0f174213b0b236a6200372942022-12-21T19:59:49ZengBMCBMC Medical Genomics1755-87942010-12-01315910.1186/1755-8794-3-59Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expressionYonneau LaurentMéjean ArnaudDenoux YvesGiraud SophieGad SophieNordenskjöld MagnusBergerheim UlfAly MarkusZickert PeterSääf AnnikaYang Ximing JChen JindongDykema Karl JNiemi Natalie MPetillo DavidKlomp Jeff AVasiliu ViorelRichard StéphaneMacKeigan Jeffrey PTeh Bin TFurge Kyle A<p>Abstract</p> <p>Background</p> <p>Germline mutations in the <it>folliculin </it>(<it>FLCN</it>) gene are associated with the development of Birt-Hogg-Dubé syndrome (BHDS), a disease characterized by papular skin lesions, a high occurrence of spontaneous pneumothorax, and the development of renal neoplasias. The majority of renal tumors that arise in BHDS-affected individuals are histologically similar to sporadic chromophobe renal cell carcinoma (RCC) and sporadic renal oncocytoma. However, most sporadic tumors lack <it>FLCN </it>mutations and the extent to which the BHDS-derived renal tumors share genetic defects associated with the sporadic tumors has not been well studied.</p> <p>Methods</p> <p>BHDS individuals were identified symptomatically and <it>FLCN </it>mutations were confirmed by DNA sequencing. Comparative gene expression profiling analyses were carried out on renal tumors isolated from individuals afflicted with BHDS and a panel of sporadic renal tumors of different subtypes using discriminate and clustering approaches. qRT-PCR was used to confirm selected results of the gene expression analyses. We further analyzed differentially expressed genes using gene set enrichment analysis and pathway analysis approaches. Pathway analysis results were confirmed by generation of independent pathway signatures and application to additional datasets.</p> <p>Results</p> <p>Renal tumors isolated from individuals with BHDS showed distinct gene expression and cytogenetic characteristics from sporadic renal oncocytoma and chromophobe RCC. The most prominent molecular feature of BHDS-derived kidney tumors was high expression of mitochondria-and oxidative phosphorylation (OXPHOS)-associated genes. This mitochondria expression phenotype was associated with deregulation of the PGC-1α-TFAM signaling axis. Loss of <it>FLCN </it>expression across various tumor types is also associated with increased nuclear mitochondrial gene expression.</p> <p>Conclusions</p> <p>Our results support a genetic distinction between BHDS-associated tumors and other renal neoplasias. In addition, deregulation of the PGC-1α-TFAM signaling axis is most pronounced in renal tumors that harbor <it>FLCN </it>mutations and in tumors from other organs that have relatively low expression of <it>FLCN</it>. These results are consistent with the recently discovered interaction between FLCN and AMPK and support a model in which FLCN is a regulator of mitochondrial function.</p>http://www.biomedcentral.com/1755-8794/3/59 |
| spellingShingle | Yonneau Laurent Méjean Arnaud Denoux Yves Giraud Sophie Gad Sophie Nordenskjöld Magnus Bergerheim Ulf Aly Markus Zickert Peter Sääf Annika Yang Ximing J Chen Jindong Dykema Karl J Niemi Natalie M Petillo David Klomp Jeff A Vasiliu Viorel Richard Stéphane MacKeigan Jeffrey P Teh Bin T Furge Kyle A Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression BMC Medical Genomics |
| title | Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression |
| title_full | Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression |
| title_fullStr | Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression |
| title_full_unstemmed | Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression |
| title_short | Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression |
| title_sort | birt hogg dube renal tumors are genetically distinct from other renal neoplasias and are associated with up regulation of mitochondrial gene expression |
| url | http://www.biomedcentral.com/1755-8794/3/59 |
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