The literature database has been updated with three papers:
Basic research:
Wong and Harbottle report the successful use of a Scaffold/Matrix Attachment Region (S/MAR) DNA vector to reintroduce a functional copy of the FLCN gene in to FLCN-null cells. Characterisation of the UOK257 cells carrying the S/MAR plasmid (UOK257-FS) showed that expression of the FLCN protein was 16-fold higher than the parental cell line, meaning that FLCN expression had been successfully reconstituted in these cells. UOK257-FS cells displayed reduced cell-cell contact, increased TGF-β signalling, reduced cell proliferation rates, and reduced mTOR signalling under serum-starved conditions, compared to the parental UOK257 cell line, indicating that FLCN function had also been reinstated in these cells. Xenograpft experiments also showed that UOK257-FS cells had not formed tumours at 150 days post injection, unlike UOK257 cells, although cell spheroids between 0.2 – 0.5 cm2 were isolated from one animal. Subsequent RT-PCR analysis of the UOK257-FS spheroids showed that FLCN expression had been retained and that TGF-β signalling also remained elevated over at least 50 cell divisions.
This paper is available to download from the BHD Articles Library:Basic section.
Case studies:
Attinà et al. report the case of a 39 year old man, with no medical or family history of pulmonary disease, who presented in clinic with a cough and progressive dyspnoea. Chest X-ray showed a right-sided pneumothorax and a pleural tube was placed. Subesquent HRCT scans showed a residual pneumothorax and multiple thin-walled cysts in the lung parenchyma and lower lobes. A 2cm solid lesion was also observed in the left kidney and biopsy revealed this to be an oncocytic neoplasm. Genetic testing of the proband and his parents confirmed a diagnosis of BHD (c.1285delC) and that the mutation had been paternally inherited.
Nakamura et al. report the case of a 56 year old man who presented with a 9.8cm renal tumour and bilateral pulmonary metastases. Radical nephrectomy was performed and histological analysis of the tumour revealed it to be a grade 2 papillary RCC. The patient was treated sequentially with IL-2, interferon-α and oral S-1 for a total of 34 months. The patient had a medical history of fibrofolliculomas, pulmonary cysts and spontaneous pneumothorax and genetic testing confirmed a diagnosis of BHD (c.1285dupC). Upon diagnosis, the patient was treated sequentially with sorafenib, sunitinib and everolimus for a total of 12 month, with the longest progression free interval during everolimus treatment (7 mo, PD). In the treatment of sporadic kidney cancers, TKIs generally have longer progression free intervals than mTOR inhibitors. However, this patient’s case suggests that mTOR inhibition may be a better treatment for BHD-associated renal cancers than TKIs, consistent with FLCN’s putative role in mTOR signalling.
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