Open Access Research article

Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression

Jeff A Klomp1, David Petillo2, Natalie M Niemi3, Karl J Dykema1, Jindong Chen2, Ximing J Yang4, Annika Sääf5, Peter Zickert6, Markus Aly7, Ulf Bergerheim8, Magnus Nordenskjöld5, Sophie Gad9, Sophie Giraud1011, Yves Denoux12, Laurent Yonneau13, Arnaud Méjean1114, Viorel Vasiliu1115, Stéphane Richard9, Jeffrey P MacKeigan3, Bin T Teh162 and Kyle A Furge12*

Author Affiliations

1 Laboratory of Computational Biology, Van Andel Research Institute, Grand Rapids, MI, USA

2 Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI, USA

3 Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, MI, USA

4 Division of Surgical Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

5 Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet at Karolinska University Hospital, SE-171 76 Stockholm, Sweden

6 Department of Pathology, Karolinska University Hospital, SE-182 88 Stockholm, Sweden

7 Division of Urology, Department of Clinical Sciences, Karolinska Institutet at Danderyd Hospital, SE-182 88 Stockholm, Sweden

8 Department of Surgery, Karolinska Institutet at Danderyd Hospital, SE-182 88 Stockholm, Sweden

9 Génétique Oncologique EPHE, INSERM U753, Le Kremlin-Bicêtre and Institut Gustave Roussy, Villejuif, France

10 Laboratoire de Génétique, Hôpital Edouard Herriot, Hospices Civils, Lyon, France

11 Centre de Références Cancers Rares PREDIR de l'INCa, Service d'Urologie, AP-HP, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France

12 Laboratoire d'Anatomie Pathologique, Hôpital Foch, Suresnes, France

13 Service d'Urologie, Hôpital Foch, Suresnes, France

14 Service d'Urologie, Hôpital Necker, Paris, France

15 Laboratoire d'Anatomie Pathologique, Hôpital Necker, Paris, France

16 NCCS-VARI Translational Research Laboratory, National Cancer Centre of Singapore, Singapore

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BMC Medical Genomics 2010, 3:59  doi:10.1186/1755-8794-3-59

Published: 16 December 2010



Germline mutations in the folliculin (FLCN) 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 FLCN mutations and the extent to which the BHDS-derived renal tumors share genetic defects associated with the sporadic tumors has not been well studied.


BHDS individuals were identified symptomatically and FLCN 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.


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 FLCN expression across various tumor types is also associated with increased nuclear mitochondrial gene expression.


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 FLCN mutations and in tumors from other organs that have relatively low expression of FLCN. 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.