Annual review 2015

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With the end of the year fast approaching, we thought we would use this week’s blog to review the studies we’ve particularly enjoyed writing about.

In the spring Iribe et al. characterised the expression patterns in BHD renal tumours with Furuya et al. focusing on FLCN and GPNMB expression. The development of a screening panel for inherited tumours associated with FLCN mutations, rather than sporadic tumours, would enable pathologists to identify BHD patients earlier. This would help ensure they receive optimal future monitoring and treatment.

In June Chen et al. published details of a new tissue specific FLCN-deficient mouse model which develops bilateral renal cysts and tumours within one year. These mice live significantly longer than other kidney-specific FLCN knockout mice enabling longer term study of tumourigenesis. The tumourigenic potential of renal cyst cells from another mouse models was confirmed by Wu et al.  this year; after in vitro culture cells formed into sarcomatoid RCCs.

Tumours derived in both of these mouse models responded to treatment with the mTOR inhibitor rapamycin. Based on studies like these a stage II clinical trial of Everolimus (a rapamycin derivative) in BHD patients with RCC was announced in July.

In the autumn studies in the C. elegans BHD model identified a role for FLCN-1 in modulating resistance to hyperosmotic stress. Possik et al. determined that flcn-1 knockout worms could resist hyperosmotic stress due to increased glycogen accumulation and rapid osmolyte production. As such glycogen deposits could have dual roles in tumourigenesis as an energy source and protection from stress.

Towards the end of the year two groups reported on the structure and function of the yeast orthologues of FLCN and FNIP1/2 – Lst7 and Lst4. Lst4 was confirmed as a DENN-family protein by Pacitto et al. who used X-ray crystallography to solve the 3D structure. The role of Lst7-Lst4 in stimulating TORC1 activity was further elucidated by Peli-Gulli et al. – Lst7-Lst4 complexes recapitulate the reported function of FLCN-FNIP2 at the lysosomal membrane where they act as a GAP to stimulate mTOR signalling.

A recurring theme in BHD research this year has been using CT screening for pulmonary cysts to identify potential BHD patients in pneumothorax and RCC patients. Several reviews of imaging in cystic lung diseases including BHD have also helped raise awareness (Ha et al., 2015, Gupta et al., 2015, Richards et al., 2015, Ferreira Francisco et al., 2015).

Early in the year Johannesma et al. identified FLCN mutations in 7.5% of primary spontaneous pneumothorax (PSP) patients – all of whom had pulmonary cysts below the carina. Ding et al. also identified and mapped large intragenic FLCN deletions in PSP families with characteristic pulmonary cysts. More recently Johannesma et al. screened RCC patients for pulmonary cysts to determine if they could identify BHD patients; no new patients were identified but the presence of multiple cysts in the lower regions of RCC patient lungs, especially those with a family history, could still be key in differential diagnosis.

In addition to the research in September Professor Gennady Bratslavsky and Dr Mehdi Mollapour organised and ran the very successful Sixth BHD Symposium and First International Upstate Kidney Cancer Symposium in New York. Summaries of the scientific & clinical and patient & family member sessions are available online.

These topics are just a selection of those published in 2015, and we at the BHD Foundation are very much looking forward to seeing how the field develops in 2016. We wish all our readers a very Happy New Year.

  • Chen J, Huang D, Rubera I, Futami K, Wang P, Zickert P, Khoo SK, Dykema K, Zhao P, Petillo D, Cao B, Zhang Z, Si S, Schoen SR, Yang XJ, Zhou M, Xiao GQ, Wu G, Nordenskjöld M, Tauc M, Williams BO, Furge KA, Teh BT. Disruption of tubular Flcn expression as a mouse model for renal tumor induction. Kidney Int. 2015 Nov;88(5):1057-69. PMID: 26083655.
  • Ding Y, Zhu C, Zou W, Ma D, Min H, Chen B, Ye M, Pan Y, Cao L, Wan Y, Zhang W, Meng L, Mei Y, Yang C, Chen S, Gao Q, Yi L. FLCN intragenic deletions in Chinese familial primary spontaneous pneumothorax. Am J Med Genet A. 2015 May;167A(5):1125-33. PMID: 25807935.
  • Ferreira Francisco FA, Soares Souza A Jr, Zanetti G, Marchiori E. Multiple cystic lung disease. Eur Respir Rev. 2015 Dec;24(138):552-64. PMID: 26621970.
  • Furuya M, Hong SB, Tanaka R, Kuroda N, Nagashima Y, Nagahama K, Suyama T, Yao M, Nakatani Y. Distinctive expression patterns of glycoprotein non-metastatic B and folliculin in renal tumors in patients with Birt-Hogg-Dubé syndrome. Cancer Sci. 2015 Mar;106(3):315-23. PMID: 25594584.
  • Gupta N, Vassallo R, Wikenheiser-Brokamp KA, McCormack FX. Diffuse Cystic Lung Disease. Part II. Am J Respir Crit Care Med. 2015 Jul 1;192(1):17-29. Review. PMID: 25906201.
  • Ha D, Yadav R, Mazzone PJ. Cystic lung disease: systematic, stepwise diagnosis. Cleve Clin J Med. 2015 Feb;82(2):115-27. Review. PMID: 25897602.
  • Iribe Y, Kuroda N, Nagashima Y, Yao M, Tanaka R, Gotoda H, Kawakami F, Imamura Y, Nakamura Y, Ando M, Araki A, Matsushima J, Nakatani Y, Furuya M. Immunohistochemical characterization of renal tumors in patients with Birt-Hogg-Dubé syndrome. Pathol Int. 2015 Mar;65(3):126-32. PMID: 25597876.
  • Johannesma PC, Reinhard R, Kon Y, Sriram JD, Smit HJ, van Moorselaar RJ, Menko FH, Postmus PE; Amsterdam BHD working group. Prevalence of Birt-Hogg-Dubé syndrome in patients with apparently primary spontaneous pneumothorax. Eur Respir J. 2015 Apr;45(4):1191-4. PMID: 25537564.
  • Johannesma PC, Houweling AC, Menko FH, van de Beek I, Reinhard R, Gille JJ, van Waesberghe JT, Thunnissen E, Starink TM, Postmus PE, van Moorselaar RJ. Are lung cysts in renal cell cancer (RCC) patients an indication for FLCN mutation analysis? Fam Cancer. 2015b Nov 24. [Epub ahead of print] PMID: 26603437.
  • Schmidt LS, & Linehan WM (2015). Clinical Features, Genetics and Potential Therapeutic Approaches for Birt-Hogg-Dubé Syndrome. Expert opinion on orphan drugs, 3 (1), 15-29 PMID: 26581862
  • Pacitto A, Ascher DB, Wong LH, Blaszczyk BK, Nookala RK, Zhang N, Dokudovskaya S, Levine TP, Blundell TL. Lst4, the yeast Fnip1/2 orthologue, is a DENN-family protein. Open Biol. 2015 Dec;5(12). pii: 150174. PMID: 26631379.
  • Péli-Gulli MP, Sardu A, Panchaud N, Raucci S, De Virgilio C. Amino Acids Stimulate TORC1 through Lst4-Lst7, a GTPase-Activating Protein Complex for the Rag Family GTPase Gtr2. Cell Rep. 2015 Oct 6;13(1):1-7. PMID: 26387955.
  • Possik E, Ajisebutu A, Manteghi S, Gingras MC, Vijayaraghavan T, Flamand M, Coull B, Schmeisser K, Duchaine T, van Steensel M, Hall DH, Pause A. FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores. PLoS Genet. 2015 Oct 6;11(10):e1005520. PMID: 26439621.
  • Richards JC, Lynch DA, Chung JH. Cystic and nodular lung disease. Clin Chest Med. 2015 Jun;36(2):299-312, ix. Review. PMID: 26024606.
  • Wu M, Si S, Li Y, Schoen S, Xiao GQ, Li X, Teh BT, Wu G, Chen J. Flcn-deficient renal cells are tumorigenic and sensitive to mTOR suppression. Oncotarget. 2015 Oct 20;6(32):32761-73. PMID: 26418749.
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