Much like BHD, Cowden syndrome (CS) is an autosomal dominant disorder which leads to benign cutaneous lesions and an increased risk of cancer. CS is caused by mutations in PTEN, and its similarities with BHD syndrome have been discussed in a previous blog post. In particular, both BHD and CS patients develop oncocytic tumours, which are epithelial in origin and have an abnormal accumulation of mitochondria. Interestingly, a recent study observed that a parotid and thyroid oncocytoma from a BHD and CS patient respectively were heterozygous for both FLCN and PTEN, which suggests that this double heterozygosity may play a role in syndromic oncocytic tumours (Pradella et al., 2013).
In this study, Pradella et al. noted that a BHD patient with fibrofolliculomas, lung cysts and a history of pneumothorax also had a parotid oncocytoma. Routine peripheral blood sequencing identified a germline heterozygous mutation in FLCN. To assess whether a complete loss of FLCN caused the development of this parotid oncocytoma, the authors carried out exon sequencing and copy number analysis, but did not detect a loss of the wild-type FLCN allele in the tumour. Mitochondrial DNA (mtDNA) mutations are often discovered in sporadic oncocytomas (Gasparre et al., 2011), however, sequencing of the mtDNA only detected common polymorphisms. The authors also noted that there were no mutations in a number of common nuclear oncogenes, such as PIK3CA, BRAF, CTNNB1, KRAS, HRAS, AKT, KIT, PIK3R1 and ERBB2. The tumour-suppressor genes PTEN and TP53 were then analysed and a somatic deletion of one PTEN allele was observed in the tumour. Array-comparative genomic hybridization confirmed that there was a specific deletion in chromosome 10 which spanned PTEN, with no other major genetic abnormalities detected within the sample.
In light of this finding, the authors returned to a thyroid oncocytoma from a CS patient which had a germline heterozygous PTEN mutation (Pradella et al., 2011), and found the tumour also carried a somatic deletion of FLCN. Molecular karyotyping of the CS oncocytoma revealed a number of chromosomal aberrations, including a deletion in chromosome 10q encompassing PTEN, and a partial loss of chromosome 17p encompassing FLCN. Considering that FNIP1 is located on chromosome 5, it is worth noting that two large duplications in chromosomes 5 and 7 were also observed – as considered in a previous blog post, could this play a part in tumourigenesis?
Finally, no FLCN and/or PTEN mutations were detected in 22 cases of mtDNA-associated sporadic oncocytoma, suggesting that this double heterozygosity may be associated with syndromic oncocytic tumours. As illustrated in our signalling diagram, PTEN and FLCN are known to modulate mTOR signalling. Furthermore, mTORC1 and FLCN are known to affect PGC1a (Cunningham et al., 2007; Klomp et al., 2010; Hasumi et al., 2012), which promotes mitochondrial biogenesis and could provide a mechanism for the mitochondrial hyperplasia seen during oncocytic transformation. However, further research is necessary, for example – could a similar process be taking place within the BHD-associated parotid oncocytomas described here?
- Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature. 2007 Nov 29;450(7170):736-40. PMID: 18046414
- Gasparre G, Romeo G, Rugolo M, Porcelli AM. Learning from oncocytic tumors: Why choose inefficient mitochondria? Biochim Biophys Acta. 2011 Jun;1807(6):633-42. PMID: 20732299
- Hasumi H, Baba M, Hasumi Y, Huang Y, Oh H, Hughes RM, Klein ME, Takikita S, Nagashima K, Schmidt LS, & Linehan WM (2012). Regulation of Mitochondrial Oxidative Metabolism by Tumor Suppressor FLCN. Journal of the National Cancer Institute, 104 (22), 1750-64 PMID: 23150719
- Klomp JA, Petillo D, Niemi NM, Dykema KJ, Chen J, Yang XJ, Sääf A, Zickert P, Aly M, Bergerheim U, Nordenskjöld M, Gad S, Giraud S, Denoux Y, Yonneau L, Méjean A, Vasiliu V, Richard S, MacKeigan JP, Teh BT, & Furge KA (2010). 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, 3 PMID: 21162720
- Pradella LM, Lang M, Kurelac I, Mariani E, Guerra F, Zuntini R, Tallini G, Mackay A, Reis-Filho JS, Seri M, Turchetti D, Gasparre G. Where Birt-Hogg-Dubé meets Cowden Syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours. Eur J Hum Genet. 2013 Feb 6. PMID: 23386036
- Pradella LM, Zuntini R, Magini P, Ceccarelli C, Neri I, Cerasoli S, Graziano C, Gasparre G, Turchetti D. Two distinct thyroid tumours in a patient with Cowden syndrome carrying both a 10q23 and a mitochondrial DNA germline deletion. J Med Genet. 2011 Nov;48(11):779-82. PMID: 21926107
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.