BackgroundGermline 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.MethodsBHDS 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.ResultsRenal 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.ConclusionsOur 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.

OBJECTIVE To evaluate the oncological outcome and functional results of prostate‐sparing cystectomy (PSC), proposed for treating bladder cancer, used since 1999 in our institution in an attempt to preserve male sexuality and to increase continence after cystectomy. PATIENTS AND METHODS Between January 1999 and December 2001, 111 men were candidates for cystectomy; 42 were selected for a prostatic capsule‐ and seminal‐sparing cystectomy with orthotopic urinary diversion. All patients had clinically organ‐confined tumours (clinical stage ≤ T2, N0M0). The first stage of the procedure was a transurethral resection of the prostate to exclude the involvement of transitional cell carcinoma (TCC) in the prostate. RESULTS Eight patients were excluded from PSC because they had TCC (seven) or prostate adenocarcinoma (one). The mean age of the remaining 34 patients was 61 years and all underwent PSC. After a mean follow‐up of 26 months, seven patients (21%) had a recurrence; one developed a local recurrence, there were widespread metastases in six (18%), and five had histologically confirmed organ‐confined tumour (T1‐2N0M0). Rates for daytime and night‐time continence were 90% and 85%, and in 29 patients potency was unchanged. CONCLUSION These early results suggest that PSC is not equivalent to radical cystoprostatectomy for bladder cancer control, despite marked improvements in the functional results. Moreover, in carefully selected patients this approach appears to dramatically increase an unusually high metastasis rate. Therefore, the indications for PSC should be either clearly well defined or abandoned in these patients.

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