234 posts · 120,112 views
BHD Research Blog is the official blog of BHDSyndrome.org, 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.
Danielle Stevenson
234 posts
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- August 26, 2016
- 05:03 AM
- 80 views
A new Birt-Hogg-Dubé Syndrome review
by Joana Guedes in BHD Research Blog
Gupta et al. (2016b) recently published a review about Birt-Hogg-Dubé Syndrome (BHD) exploring the key points and research advances in genetics and pathogenesis, clinical manifestations, diagnosis and disease management.... Read more »
Gupta N, Sunwoo BY, & Kotloff RM. (2016) Birt-Hogg-Dubé Syndrome. Clinics in chest medicine, 37(3), 475-86. PMID: 27514594
- August 12, 2016
- 05:10 AM
- 165 views
Simulation study suggests that mutations induce conformational changes in FLCN - possible cause of Birt-Hogg-Dubé syndrome
by Joana Guedes in BHD Research Blog
Germline mutations of the folliculin gene are normally responsible for Birt–Hogg–Dubé (BHD) syndrome. The 3D structure of the C-terminal domain of folliculin (FLCN), folliculin-CT, has been previously determined (Nookala et al., 2012). FLCN is a tumor suppressor and a guanine nucleotide exchange factor (GEF) for Rab35. GEF activity of FLCN towards its GTPase might be essential for cellular processes. Most of the reported FLCN mutations lead to the BHD phenotype (Lim et al., 20........ Read more »
Verma S, Tyagi C, Goyal S, Pandey B, Jamal S, Singh A, & Grover A. (2016) Mutations induce conformational changes in folliculin C-terminal domain: possible cause of loss of guanine exchange factor activity and Birt-Hogg-Dubé syndrome. Journal of biomolecular structure , 1-6. PMID: 27484154
- August 5, 2016
- 05:09 AM
- 209 views
Multiple germline mutations in rare inherited cancer syndrome genes
by Joana Guedes in BHD Research Blog
A recent study by Whitworth et al. (2016) reports five new cases of multiple germline mutations in inherited cancer syndrome genes, three of them involve the combination of mutations in FLCN with NF1, TP53, and MSH2, respectively.... Read more »
Whitworth J, Skytte AB, Sunde L, Lim DH, Arends MJ, Happerfield L, Frayling IM, van Minkelen R, Woodward ER, Tischkowitz MD.... (2016) Multilocus Inherited Neoplasia Alleles Syndrome: A Case Series and Review. JAMA oncology, 2(3), 373-9. PMID: 26659639
- July 22, 2016
- 09:01 AM
- 240 views
Update on clinical trials and treatments for RCC
by Joana Guedes in BHD Research Blog
Renal cell carcinoma (RCC) is the most common type of kidney cancer and although the majority of cases are sporadic approximately 3% of cases are caused by genetic conditions such as BHD, VHL, HLRCC and TSC (Randall et al., 2014). These inherited forms of RCC have provided great insights into sporadic cancer genetics. BHD patients can develop multiple kidney tumours. In most cases these tumours are small local RCCs that can be surgically removed. However, these treatments are not without risk,........ Read more »
Randall JM, Millard F, & Kurzrock R. (2014) Molecular aberrations, targeted therapy, and renal cell carcinoma: current state-of-the-art. Cancer metastasis reviews, 33(4), 1109-24. PMID: 25365943
- July 14, 2016
- 10:14 AM
- 254 views
Folliculin is required for embryonic brain development in zebrafish
by Joana Guedes in BHD Research Blog
Birt-Hogg-Dubé syndrome (BHD) is caused by mutations in the gene encoding folliculin (FLCN). How this leads to the BHD clinical manifestations is not yet clear. Since homozygous mutations of FLCN are lethal in mice, rats and dogs at early embryonic stage (Hasumi et al., 2009), zebrafish is a valuable alternative model to study the developmental functions of FLCN. Newly published research from Kenyon et al. (2016) examines the role of FLCN in zebrafish development using morpholino oligonuc........ Read more »
Kenyon EJ, Luijten MN, Gill H, Li N, Rawlings M, Bull JC, Hadzhiev Y, van Steensel MA, Maher E, & Mueller F. (2016) Expression and knockdown of zebrafish folliculin suggests requirement for embryonic brain morphogenesis. BMC developmental biology, 16(1), 23. PMID: 27391801
- July 8, 2016
- 12:38 PM
- 302 views
FNIP1 and FNIP2 inhibit Hsp90 chaperone cycle and enhance drug binding
by Joana Guedes in BHD Research Blog
Heat shock protein-90 (Hsp90) is a molecular chaperone required for folding, stability and activity of many proteins, known as clients, including drivers of tumour initiation, progression and metastasis (Rohl et al. 2013). ATPase binding and hydrolysis is essential for the chaperone function of Hsp90. ATPase function is regulated by other proteins known as co-chaperones. In an interesting new study, Woodford et al. (2016) show that the stability of the tumour suppressor folliculin (FLCN), whose ........ Read more »
Woodford MR, Dunn DM, Blanden AR, Capriotti D, Loiselle D, Prodromou C, Panaretou B, Hughes PF, Smith A, Ackerman W.... (2016) The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding. Nature communications, 12037. PMID: 27353360
- June 17, 2016
- 05:49 AM
- 304 views
FLCN activates mTORC1 by maintaining lysosomal leucine level
by Joana Guedes in BHD Research Blog
The intracellular amino acid pool within the lysosome has been shown to activate the mTORC1 signaling pathway (Zoncu et al., 2011; Jewell et al., 2013). However, how the sequester of the signaling molecules within the lysosome occurs remains poorly understood. New research from Wu et al. (2016) shows that the suppression of FLCN, a tumour suppressor gene associated with the Birt-Hogg-Dubé (BHD) syndrome, controls mTORC1 activity by modulating the lysosomal leucine levels. FLCN exerts this new f........ Read more »
Wu X, Zhao L, Chen Z, Ji X, Qiao X, Jin Y, & Liu W. (2016) FLCN Maintains the Leucine Level in Lysosome to Stimulate mTORC1. PloS one, 11(6). PMID: 27280402
- June 10, 2016
- 06:14 AM
- 319 views
BHD syndrome and thyroid conditions
by Joana Guedes in BHD Research Blog
Dong et al., (2016) have recently reported two BHD syndrome patients also affected with papillary thyroid cancer. Lesions were bilateral and multifocal and small lymph node metastases occurred. Due to the small number of patients in the study the authors are unsure whether thyroid cancer in BHD patients is susceptible to exhibiting bilaterally and lymph node metastasis. However, they suggest considering thyroidectomy and prophylactic lymph node dissection for thyroid cancer patients with BHD. Th........ Read more »
Dong L, Gao M, Hao WJ, Zheng XQ, Li YG, Li XL, & Yu Y. (2016) Case Report of Birt-Hogg-Dubé Syndrome: Germline Mutations of FLCN Detected in Patients With Renal Cancer and Thyroid Cancer. Medicine, 95(22). PMID: 27258496
- June 3, 2016
- 11:43 AM
- 313 views
Anonymising and sharing patient data
by Joana Guedes in BHD Research Blog
Patient data is extremely valuable for biomedical and healthcare research. Collecting and sharing patient data globally can lead to several benefits such as better understanding diseases, identifying patterns in public health and disease, developing and monotoring drugs and treatments, allowing researchers to build on the work of others efficiently and finding suitable candidates to take part in clinical trials. However, concerns about privacy have been a barrier for making patient data availabl........ Read more »
El Emam K, Rodgers S, & Malin B. (2015) Anonymising and sharing individual patient data. BMJ (Clinical research ed.). PMID: 25794882
- May 27, 2016
- 12:33 PM
- 339 views
Starvation-induced FLCN association with lysosomes via a Rab34–RILP complex
by Joana Guedes in BHD Research Blog
Dynamic positioning of lysosomes in the cytoplasm plays an important role in their function and is, in part, regulated by cellular nutrient status. The FLCN/FNIP complex is known to be active on the lysosome surface, where it interacts with Rag GTPases, supports the nutrient‐dependent recruitment and activation of mTORC1, and regulates the localisation of lysosome associated transcription factors (Petit et al., 2013; Tsun et al., 2013). New research from Starling et al. (2016) now shows that f........ Read more »
Starling GP, Yip YY, Sanger A, Morton PE, Eden ER, & Dodding MP. (2016) Folliculin directs the formation of a Rab34-RILP complex to control the nutrient-dependent dynamic distribution of lysosomes. EMBO reports. PMID: 27113757
- February 26, 2016
- 04:50 AM
- 390 views
BHD pulmonary cysts: The stretch hypothesis
by Danielle Stevenson in BHD Research Blog
The majority of BHD patients develop pulmonary cysts and approximately 1 in 3 will suffer a pneumothorax. Although BHD pulmonary cysts have defining characteristics compared to other cystic lung diseases (as discussed in recent reviews), the underlying pathogenesis is not yet clearly understood. A recent review from Kennedy, Khabibullin & Henske (2016) summarises the current understanding of BHD pulmonary pathology relative to the stretch hypothesis for cyst formation.... Read more »
Kennedy JC, Khabibullin D, & Henske EP. (2016) Mechanisms of Pulmonary Cyst Pathogenesis in Birt-Hogg-Dube Syndrome: The Stretch Hypothesis. Seminars in cell . PMID: 26877139
- February 12, 2016
- 04:16 AM
- 418 views
Maintained disomic chromosome 17 as a diagnostic marker for BHD-associated chromophobe RCC
by Danielle Stevenson in BHD Research Blog
Renal cell carcinomas (RCCs) can be life-threatening and although mostly sporadic, approximately 5% are associated with genetic conditions such as BHD. Early identification of families carrying cancer-predisposing mutations enables access to regular screening and earlier treatment. However, it can be difficult to distinguish between sporadic and inherited RCC based on standard immunohistological analysis. New research from Kato et al. (2016) assessed whether variability in the chromosomal status........ Read more »
Kato, I., Iribe, Y., Nagashima, Y., Kuroda, N., Tanaka, R., Nakatani, Y., Hasumi, H., Yao, M., & Furuya, M. (2016) Fluorescent and Chromogenic in situ Hybridization of CEN17q as a Potent Useful Diagnostic Marker for Birt-Hogg-Dubé Syndrome-associated Chromophobe Renal Cell Carcinomas. Human Pathology. DOI: 10.1016/j.humpath.2016.01.004
- February 5, 2016
- 09:00 AM
- 433 views
TSC2 mutations confer everolimus sensitivity in hepatocellular carcinomas
by Danielle Stevenson in BHD Research Blog
Hepatocellular carcinomas (HCCs) are the third leading cause of cancer deaths globally; frequently diagnosed only in the advanced stages and aggressive in nature. Although enhanced mTOR activity has a key role in HCC tumourigenesis, the EVOLVE-1 clinical trial of mTOR inhibitor everolimus found no associated improvement in overall survival (Zhu et al., 2014). However, everolimus is an effective treatment for tuberous sclerosis complex (TSC) manifestations, a rare disease associated with mutation........ Read more »
Huynh H, Hao HX, Chan SL, Chen D, Ong R, Soo KC, Pochanard P, Yang D, Ruddy D, Liu M.... (2015) Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus. Molecular cancer therapeutics, 14(5), 1224-35. PMID: 25724664
- January 29, 2016
- 04:23 AM
- 471 views
A role for dermatologists in diagnosing BHD earlier
by Danielle Stevenson 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
- 04:57 AM
- 416 views
Genome-wide genetic abnormalities in BHD-RCCs
by Danielle Stevenson 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 »
Iribe Y, Yao M, Tanaka R, Kuroda N, Nagashima Y, Nakatani Y, & Furuya M. (2016) Genome-Wide Uniparental Disomy and Copy Number Variations in Renal Cell Carcinomas Associated with Birt-Hogg-Dubé Syndrome. The American journal of pathology, 186(2), 337-46. PMID: 26776076
- January 15, 2016
- 05:59 AM
- 467 views
Increased HIF-1α activity in RCC modulated by p62
by Danielle Stevenson 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
- 05:03 AM
- 585 views
HIF-2α regulates PD-L1 expression in RCC
by Danielle Stevenson 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 »
Messai Y, Gad S, Noman MZ, Le Teuff G, Couve S, Janji B, Kammerer SF, Rioux-Leclerc N, Hasmim M, Ferlicot S.... (2015) Renal Cell Carcinoma Programmed Death-ligand 1, a New Direct Target of Hypoxia-inducible Factor-2 Alpha, is Regulated by von Hippel-Lindau Gene Mutation Status. European urology. PMID: 26707870
- December 18, 2015
- 04:54 AM
- 523 views
New HLRCC patient-derived cell line to model papillary RCC
by Danielle Stevenson 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
- 04:46 AM
- 403 views
CT Screening for pulmonary cysts to identify potential BHD patients
by Danielle Stevenson 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
- 05:52 AM
- 590 views
Biomarkers in diagnosis, prognosis and treatment of RCC
by Danielle Stevenson 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 »
Mickley A, Kovaleva O, Kzhyshkowska J, & Gratchev A. (2015) Molecular and immunologic markers of kidney cancer-potential applications in predictive, preventive and personalized medicine. The EPMA journal, 20. PMID: 26500709
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