With the New Year upon us, we thought we would use this week’s blog to review the studies we’ve particularly enjoyed writing about, and to revisit emerging themes.
During the summer-autumn period, there were a number of interesting studies that shed light on the molecular function of FLCN. Firstly, Goncharova et al. reported that FLCN activates AMPK signaling via LKB1 and E-cadherin, in Alveolar Type II (ATII) cells. Conversely, both Yan et al. and Possik et al. showed that FLCN inhibits AMPK signaling in MEFs and C.elegans nematodes, and that loss of FLCN leads to tumorigenic metabolic changes consistent with the Warburg Effect. These conflicting findings were resolved in August, when Khabibullin et al. published data showing that FLCN function is highly cell-specific.
FLCN’s role in autophagy was further elucidated by Dunlop et al. who reported that FLCN modulates autophagy through its interactions with ULK1 and GABARAP; FLCN was shown to be important for cardiomyocyte development (Hasumi et al., 2014); and a hitherto unknown role for FNIP1 in iNKT cell development was reported by Park et al.
The results from the trial of Rapamycin as a treatment for fibrofolliculomas were published this year, and reported that Rapamycin was not effective (Gijezen et al., 2014).
A cohort study of 33 BHD patients with kidney cancer showed that the majority of tumours were of oncocytic, choromophobe or mixed histology, and that the median age at the diagnosis of the first tumour was 46 (Benusiglio et al., 2014). This corresponds well with a study by Schuch et al. which found that patients with a genetic predisposition to kidney cancer developed tumours nearly 25 years earlier than patients with sporadic tumours. Thus, Schuch et al. recommend that doctors should consider germline genetic testing in kidney cancer patients under the age of 46.
A number of papers regarding the lung symptoms of BHD have been published this year. In July, it was reported that BHD can cause pneumothoraces in children in rare cases (Johannesma et al., 2014a), and in September, 1 in 16 BHD patients were found to be at risk of developing a pneumothorax within 30 days of taking a commercial flight (Postmus et al. 2014). Two separate groups hypothesized that defective cell-cell adhesion made cyst walls more likely to burst under mechanical stress, leading to an accumulation of air in the pleural space and potentially causing a pneumothorax (Johannesma et al., 2014b, Kumasaka et al., 2014).
Finally, two case studies have reported that somatic FLCN mutations contributed to the development of sporadic tumours (Sirintrapun et al., 2014, Wagle et al., 2014). These studies indicate that FLCN mutations may play a wider role in disease than just causing BHD Syndrome, suggesting that BHD is a fundamental disease.
These papers are just a selection of those published in 2014, and we at the BHD Foundation are very much looking forward to seeing how the field develops in 2015. We wish all our readers a very Happy New Year.
- Benusiglio, P., Giraud, S., Deveaux, S., Méjean, A., Correas, J., Joly, D., Timsit, M., Ferlicot, S., Verkarre, V., Abadie, C., Chauveau, D., Leroux, D., Avril, M., Cordier, J., & Richard, S. (2014). Renal cell tumour characteristics in patients with the Birt-Hogg-Dubé cancer susceptibility syndrome: a retrospective, multicentre study Orphanet Journal of Rare Diseases, 9 (1) DOI: 10.1186/s13023-014-0163-z
- Dunlop EA, Seifan S, Claessens T, Behrends C, Kamps MA, Rozycka E, Kemp AJ, Nookala RK, Blenis J, Coull BJ, Murray JT, van Steensel MA, Wilkinson S, & Tee AR (2014). FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation. Autophagy, 10 (10) PMID: 25126726
- Gijezen LM, Vernooij M, Martens H, Oduber CE, Henquet CJ, Starink TM, Prins MH, Menko FH, Nelemans PJ, & van Steensel MA (2014). Topical rapamycin as a treatment for fibrofolliculomas in birt-hogg-dubé syndrome: a double-blind placebo-controlled randomized split-face trial. PloS one, 9 (6) PMID: 24910976
- Goncharova EA, Goncharov DA, James ML, Atochina-Vasserman EN, Stepanova V, Hong SB, Li H, Gonzales L, Baba M, Linehan WM, Gow AJ, Margulies S, Guttentag S, Schmidt LS, & Krymskaya VP (2014). Folliculin Controls Lung Alveolar Enlargement and Epithelial Cell Survival through E-Cadherin, LKB1, and AMPK. Cell reports, 7 (2), 412-23 PMID: 24726356
- Hasumi Y, Baba M, Hasumi H, Huang Y, Lang M, Reindorf R, Oh HB, Sciarretta S, Nagashima K, Haines DC, Schneider MD, Adelstein RS, Schmidt LS, Sadoshima J, & Marston Linehan W (2014). Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation. Human molecular genetics PMID: 24908670
- Johannesma PC, van den Borne BE, Gille JJ, Nagelkerke AF, van Waesberghe JT, Paul MA, van Moorselaar RJ, Menko FH, & Postmus PE (2014a). Spontaneous pneumothorax as indicator for Birt-Hogg-Dubé syndrome in paediatric patients. BMC pediatrics, 14 PMID: 24994497
- Johannesma PC, Houweling AC, van Waesberghe JH, van Moorselaar RJ, Starink TM, Menko FH, & Postmus PE (2014b). The pathogenesis of pneumothorax in Birt-Hogg-Dubé syndrome: A hypothesis. Respirology (Carlton, Vic.), 19 (8), 1248-50 PMID: 25302759
- Khabibullin D, Medvetz DA, Pinilla M, Hariharan V, Li C, Hergrueter A, Laucho Contreras M, Zhang E, Parkhitko A, Yu JJ, Owen CA, Huang H, Baron RM, & Henske EP (2014). Folliculin regulates cell-cell adhesion, AMPK, and mTORC1 in a cell-type-specific manner in lung-derived cells. Physiological reports, 2 (8) PMID: 25121506
- Kumasaka T, Hayashi T, Mitani K, Kataoka H, Kikkawa M, Tobino K, Kobayashi E, Gunji Y, Kunogi M, Kurihara M, & Seyama K (2014). Characterization of pulmonary cysts in Birt-Hogg-Dubé syndrome: histopathologic and morphometric analysis of 229 pulmonary cysts from 50 unrelated patients. Histopathology PMID: 24393238
- Park H, Tsang M, Iritani BM, & Bevan MJ (2014). Metabolic regulator Fnip1 is crucial for iNKT lymphocyte development. Proceedings of the National Academy of Sciences of the United States of America, 111 (19), 7066-71 PMID: 24785297
- Possik E, Jalali Z, Nouët Y, Yan M, Gingras MC, Schmeisser K, Panaite L, Dupuy F, Kharitidi D, Chotard L, Jones RG, Hall DH, & Pause A (2014). Folliculin regulates ampk-dependent autophagy and metabolic stress survival. PLoS genetics, 10 (4) PMID: 24763318
- Postmus PE, Johannesma PC, Menko FH, & Paul MA (2014). In-Flight Pneumothorax: Diagnosis May Be Missed because of Symptom Delay. American journal of respiratory and critical care medicine, 190 (6), 704-5 PMID: 25221882
- Shuch B, Vourganti S, Ricketts CJ, Middleton L, Peterson J, Merino MJ, Metwalli AR, Srinivasan R, & Linehan WM (2014). Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 32 (5), 431-7 PMID: 24378414
- Sirintrapun SJ, Geisinger KR, Cimic A, Snow A, Hagenkord J, Monzon F, Legendre BL Jr, Ghazalpour A, Bender RP, & Gatalica Z (2014). Oncocytoma-like renal tumor with transformation toward high-grade oncocytic carcinoma: a unique case with morphologic, immunohistochemical, and genomic characterization. Medicine, 93 (15) PMID: 25275525
- Wagle N, Grabiner BC, Van Allen EM, Amin-Mansour A, Taylor-Weiner A, Rosenberg M, Gray N, Barletta JA, Guo Y, Swanson SJ, Ruan DT, Hanna GJ, Haddad RI, Getz G, Kwiatkowski DJ, Carter SL, Sabatini DM, Jänne PA, Garraway LA, & Lorch JH (2014). Response and acquired resistance to everolimus in anaplastic thyroid cancer. The New England journal of medicine, 371 (15), 1426-33 PMID: 25295501
- Yan M, Gingras MC, Dunlop EA, Nouët Y, Dupuy F, Jalali Z, Possik E, Coull BJ, Kharitidi D, Dydensborg AB, Faubert B, Kamps M, Sabourin S, Preston RS, Davies DM, Roughead T, Chotard L, van Steensel MA, Jones R, Tee AR, & Pause A (2014). The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. The Journal of clinical investigation PMID: 24762438
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.