BHD Research Blog

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265 posts · 172,538 views

BHD Research Blog is the official blog of, the primary online resource for anyone interested in Birt-Hogg-Dubé Syndrome, a rare genetic condition linked to benign skin growths, collapsed lung and kidney cancers. In the BHD Research Blog, we focus on analysing current research in BHD and related fields, as well as considering wider issues relating to rare diseases.

Joana Guedes
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  • January 29, 2016
  • 05:23 AM

A role for dermatologists in diagnosing BHD earlier

by Joana Guedes in BHD Research Blog

Birt-Hogg-Dubé (BHD) syndrome was initially described as a heritable dermatological condition based on the presence of multiple fibrofolliculomas, trichodiscomas and acrochordons in a Canadian kindred (Birt et al., 1977). Now it is known that BHD patients can also develop pulmonary cysts, with an associated risk of pneumothorax, and bilateral, multifocal renal tumours. Due to the risk of tumour development it is important that patients are diagnosed early, enabling them to access regular ........ Read more »

Tellechea O, Cardoso JC, Reis JP, Ramos L, Gameiro AR, Coutinho I, & Baptista AP. (2015) Benign follicular tumors. Anais brasileiros de dermatologia, 90(6), 780-98. PMID: 26734858  

  • January 22, 2016
  • 05:57 AM

Genome-wide genetic abnormalities in BHD-RCCs

by Joana Guedes in BHD Research Blog

Renal cell carcinoma (RCC) can be sporadic or associated with inherited mutations. These tumours frequently carry additional genetic abnormalities including copy number variations, deletions and amplifications. Although not all tumours have an altered genetic profile, sporadic RCC subtypes have common cytogenetic patterns. New research from Iribe et al. (2016) assessed several RCC subtypes from BHD patients to determine if they have similar or distinct patterns of genetic abnormalities.... Read more »

  • January 15, 2016
  • 06:59 AM

Increased HIF-1α activity in RCC modulated by p62

by Joana Guedes in BHD Research Blog

Clear cell Renal Cell Carcinoma (ccRCC) is frequently associated with the loss of VHL, but gain of chromosome 5q35.3 – which contains the oncogene SQSTM1 – was also found in approximately 70% of tumours (Li et al., 2013). The SQSTM1 protein, p62, is a scaffold protein involved in cellular processes and signalling pathways related to malignant growth. New research from Chen et al., (2015) determined a role for p62 in regulating glucose metabolism, through HIF-1α signalling.... Read more »

Chen K, Zeng J, Xiao H, Huang C, Hu J, Yao W, Yu G, Xiao W, Xu H, & Ye Z. (2016) Regulation of glucose metabolism by p62/SQSTM1 through HIF1α. Journal of cell science. PMID: 26743088  

  • January 8, 2016
  • 06:03 AM

HIF-2α regulates PD-L1 expression in RCC

by Joana Guedes in BHD Research Blog

Tumour cells can create immunosuppressive microenvironments by hijacking natural mechanisms such as PD-L1 expression to impair T-cell function. Several new immunotherapy treatments target the PD-1/PD-L1 pathway and have produced some long-lasting responses in patients (Motzer et al., 2015) but not all patients respond. High expression of PD-L1 in clear cell RCC (ccRCC) has been shown to correlate with metastasis and poor outcome (Thompson et al., 2007). New research from Messai et al. (2015) has........ Read more »

  • December 18, 2015
  • 05:54 AM

New HLRCC patient-derived cell line to model papillary RCC

by Joana Guedes in BHD Research Blog

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare genetic condition caused by mutations in fumarate hydratase (FH). HLRCC patients are at risk of developing type 2 papillary renal cell carcinoma (pRCC2) which typically has an early onset with high metastatic potential. Existing targeted treatments have very limited response rates in both primary and metastatic pRCC2 tumours. Developing more effective treatments relies on preclinical models such as the new FH-deficient cell lin........ Read more »

Perrier-Trudova V, Huimin BW, Kongpetch S, Huang D, Ong P, LE Formal A, Poon SL, Siew EY, Myint SS, Gad S.... (2015) Fumarate Hydratase-deficient Cell Line NCCFH1 as a New In Vitro Model of Hereditary Papillary Renal Cell Carcinoma Type 2. Anticancer research, 35(12), 6639-53. PMID: 26637880  

  • December 4, 2015
  • 05:46 AM

CT Screening for pulmonary cysts to identify potential BHD patients

by Joana Guedes in BHD Research Blog

As discussed in our blog post from the beginning of this year a greater level of BHD awareness among pulmonologists and associated professionals could help increase early diagnoses. It has been reported that up to 10% of spontaneous pneumothorax patients are carrying FLCN mutations (Ren et al., 2008, Johannesma et al., 2015, Ding et al., 2015). The identification of BHD in these patients results in screening for the development of renal cell carcinoma in patients and their families leading to ea........ Read more »

Ferreira Francisco FA, Soares Souza A Jr, Zanetti G, & Marchiori E. (2015) Multiple cystic lung disease. European respiratory review : an official journal of the European Respiratory Society, 24(138), 552-64. PMID: 26621970  

Johannesma PC, Houweling AC, Menko FH, van de Beek I, Reinhard R, Gille JJ, van Waesberghe JT, Thunnissen E, Starink TM, Postmus PE.... (2015) Are lung cysts in renal cell cancer (RCC) patients an indication for FLCN mutation analysis?. Familial cancer. PMID: 26603437  

  • November 27, 2015
  • 06:52 AM

Biomarkers in diagnosis, prognosis and treatment of RCC

by Joana Guedes in BHD Research Blog

Tumour biomarkers are measurable changes in cancer cells that could be used to improve available therapies. The identification of early biomarkers could increase early diagnosis rates and provide insight into tumour biology including aggressiveness. In addition tumour subtype-specific biomarkers could help identify the treatments most likely to be effective and also be used to measure response. The search for biomarkers in renal cell carcinoma (RCC) is an active field, with various types of pote........ Read more »

  • November 20, 2015
  • 09:37 AM

Summary of recent kidney cancer clinical trials

by Joana Guedes in BHD Research Blog

Kidney tumours, if detected early enough, can often be removed surgically without the need for further drug treatments. However, if the primary tumour metastasises traditional chemotherapies and radiotherapies become ineffective and patient survival is limited. In recent years there have been great advances in treatments for metastatic renal cell carcinoma (mRCC) with several targeted treatments now available. However, these targeted treatments show variable response rates and efficacy. This blo........ Read more »

Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER.... (2015) Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. The New England journal of medicine, 373(19), 1803-13. PMID: 26406148  

  • November 13, 2015
  • 07:07 AM

FLCN modifies the cytoplasmic translocation and aggregation of TDP-43

by Joana Guedes in BHD Research Blog

TDP-43 is a DNA/RNA binding protein whose cytoplasmic aggregation is associated with neuronal death in ALS and frontotemporal lobar degeneration (FTLD). TDP-43 has multiple cellular functions and shuttles between the nucleus and cytoplasm. However, in ALS and FTLD nuclear clearance of TDP-43 results in increased cytoplasmic localisation – a precursor to TDP-43 aggregation and stress granule formation. The mechanisms that regulate TDP-43 transport are not well understood but new research fr........ Read more »

  • November 6, 2015
  • 06:25 AM

In response to amino acids yeast FLCN-FNIP orthologues Lst7-Lst4 stimulate TORC1 activity

by Joana Guedes in BHD Research Blog

In eukaryotic cells TORC1 signalling has a key role in controlling cell growth in response to nutritional status. Folliculin (FLCN) and the FNIP proteins regulate mTORC signalling via interactions with Rag family GTPases (Petit et al., 2013, Tsun et al., 2012). Recently Péli-Gulli et al. (2015) reported that the yeast orthologues of FLCN and FNIP, Lst7 and Lst4, form a heterodimer that acts as a GTPase Activating Protein (GAP) for yeast Rag family GTPase Gtr2 . Lst4-Lst7 is the first GAP ........ Read more »

  • October 30, 2015
  • 10:00 AM

Pleural covering as an alternative treatment for recurrent pneumothorax

by Joana Guedes in BHD Research Blog

Most BHD patients develop pulmonary cysts and although only 30-35% will suffer a pneumothorax the recurrence rate is very high (Toro et al., 2008). The standard treatment for recurrent pneumothorax is pleurodesis, sometimes accompanied with pleurectomy, which attaches the lung surface to the chest wall thereby reducing the risk of further air leaks. An alternative treatment pioneered by several independent groups of researchers and clinicians in Japan is pleural covering which reinforces the sur........ Read more »

Ebana H, Otsuji M, Mizobuchi T, Kurihara M, Takahashi K, & Seyama K. (2015) Pleural Covering Application for Recurrent Pneumothorax in a Patient with Birt-Hogg-Dubé Syndrome. Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia. PMID: 26370712  

  • October 16, 2015
  • 05:12 AM

A role for FLCN in modulating resistance to hyperosmotic stress

by Joana Guedes in BHD Research Blog

Water efflux in response to hyperosmotic stress causes cells to shrink, protein and DNA damage, cell cycle arrest and death. Cells must therefore adapt to changes in external osmolality; one conserved mechanism is to increase intracellular osmolytes to maintain osmotic homeostasis. New research from Possik et al., (2015) has identified a role for FLCN-1, mediated by AMPK activity, in the maintenance of glycogen stores required for rapid production of the osmolyte glycerol in C.elegans.... Read more »

Possik E, Ajisebutu A, Manteghi S, Gingras MC, Vijayaraghavan T, Flamand M, Coull B, Schmeisser K, Duchaine T, van Steensel M.... (2015) FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores. PLoS genetics, 11(10). PMID: 26439621  

  • October 9, 2015
  • 10:00 AM

Flcn-deficient renal cyst cells can be tumourigenic

by Joana Guedes in BHD Research Blog

Kidney-specific Flcn knockout in mice results in the development of large polycystic kidneys and uremia causing renal failure and death within three weeks (Chen et al., 2008). As this short time frame is insufficient for substantial solid tumour growth Wu et al., (2015) extracted renal cyst cells to assess their tumourigenic potential and response to mTOR inhibitors.... Read more »

  • September 18, 2015
  • 05:19 AM

Use of Cavitation Ultrasonic Surgical Aspirators for partial nephrectomies

by Joana Guedes in BHD Research Blog

Partial nephrectomies are technically challenging surgeries but preserve healthy renal tissue and therefore function. To minimise bleeding the major blood vessels are usually clamped and tumour extraction completed under ischemic conditions – the renal tissue is deprived of oxygen and nutrients due to restricted blood flow. Although ischemic conditions for less than 25 minutes have minimal reported impact on renal function (Volpe et al., 2015), more complex tumours result in prolonged isch........ Read more »

  • September 11, 2015
  • 10:00 AM

Upcoming BHD and Upstate Kidney Cancer Symposium

by Joana Guedes in BHD Research Blog

On September 23-26th the Sixth BHD and First Upstate Kidney Cancer Symposium will be taking place in Syracuse, New York. Hosted by Dr Medhi Mollapour and Professor Gennady Bratslavsky of the Upstate Medical University (both also presenting), it will focus on scientific and clinical developments in BHD and renal cell cancer.... Read more »

  • September 4, 2015
  • 07:08 AM

Everolimus for the treatment of lymphangioleiomyomatosis

by Joana Guedes in BHD Research Blog

mTOR is dysregulated in a range of tumour types and can be targeted with mTOR inhibitor treatments such as everolimus and sirolimus. Tuberous sclerosis complex (TSC) and sporadic lymphangioleiomyamatosis (LAM) result from mutations in TSC1 or TSC2 that disrupt mTOR signalling (Carsillo et al., 2000, Glasgow et al., 2010). The associated aberrant cell growth, survival and movement results in the formation of slow growing tumours in various tissues and pulmonary cyst formation with loss of pulmona........ Read more »

Goldberg HJ, Harari S, Cottin V, Rosas IO, Peters E, Biswal S, Cheng Y, Khindri S, Kovarik JM, Ma S.... (2015) Everolimus for the treatment of lymphangioleiomyomatosis: a phase II study. The European respiratory journal, 46(3), 783-94. PMID: 26113676  

  • August 28, 2015
  • 10:00 AM

Immunotherapy AGS-003 trial in localised renal cell carcinoma

by Joana Guedes in BHD Research Blog

Although targeted therapies have enhanced the efficiency of renal cell carcinoma (RCC) treatment, individual responses are usually limited with few complete remissions reported. An expanding therapy field in RCC is immunotherapy – small molecule and autologous treatments that can modulate the immune system to kill cancer cells. Although to date immunotherapies have only induced a response in a subpopulation of patients, a greater proportion of these responses are long lasting highlighting ........ Read more »

  • August 21, 2015
  • 10:00 AM

TDP-43 differentially splices FNIP1

by Joana Guedes in BHD Research Blog

Folliculin interaction protein 1 (FNIP1), through interactions with FLCN, plays a role in a range of cellular processes (Baba et al., 2006). Alternative splicing of FNIP1, under the control of MBNL1, was previously reported in late mesenchymal differentiation (Venables et al., 2013). New research from De Conti et al., (2015) has identified FNIP1 as also being differentially spliced by TDP-43 – a protein associated with neurodegeneration in ALS and fronto-temporal dementia (Neumann et al., ........ Read more »

  • August 14, 2015
  • 10:00 AM

Sharing genomic data to advance research

by Joana Guedes in BHD Research Blog

It is expected that genetic sequencing will advance both specialised and general healthcare leading to more personalised care based on an individual’s genome. It can be used to identify disease-specific mutations and those associated with more complex conditions. However, as discussed previously on this blog, understanding the effect of a single mutation can be difficult without comparison between healthy and disease patient samples. Sharing patient data accumulated by private and academic........ Read more »

  • August 7, 2015
  • 10:00 AM

High-throughput screening to identify synthetic lethal compounds in RCC

by Joana Guedes in BHD Research Blog

Synthetic lethal compounds selectively kill cancer cells by targeting tumour cell-essential processes, but leave healthy cells unharmed. Research is ongoing to identify such compounds in a range of cancers (reviewed in McLornan et al., 2014) including renal cell carcinoma (RCC). New research from Wolff et al., (2015) has identified homoharringtonine (HHT) as synthetically lethal for a subset of clear cell RCC (ccRCC) tumours associated with VHL mutations.... Read more »

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