Syndromic oncocytic tumours: BHD meets Cowden syndrome

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?


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