Computational approaches may expedite drug repurposing for rare diseases

Drug repurposing is predicated on the fact that many diseases are caused by the dysregulation of similar signaling pathways, or that drugs may affect several biological targets at once, meaning that a single drug may be able to treat multiple diseases. Repurposing an existing drug is easier, cheaper and faster than developing a brand new drug, as there are comparatively few research and development costs, and the drug is already known to be effective and safe for use in patients.

Currently, the vast majority of additional indications for existing drugs have been found by chance (Liu et al., 2013). However, as technology improves, researchers have developed high throughput in silico methods to analyse the structures and biological activities of existing drugs to identify new indications (Ekins et al., 2011, Liu et al., 2013). A recent study by Gramatica et al. (2014) report an alternative approach, using computational linguistics and graph theory to identify previously unknown links between drugs and diseases.

Gramatica et al. analysed three million publication abstracts relating to 300 rare diseases from the PubMed literature database. Analysing the language in the abstracts allowed the researchers to build visual networks linking different types of node, such as disease, protein, biological process, or drug. To show how these networks were built, the researchers used an example from a paper describing the pathogenesis of lymphangioleimyomatosis (LAM).

Each sentence was analysed independently, the nodes highlighted, and arranged into a network with each node linked pairwise, like so:

 Picture1 1024x308 Computational approaches may expedite drug repurposing for rare diseases

Each separate network was then rearranged to form a single, larger network representing the whole paper:

 Picture2 1024x302 Computational approaches may expedite drug repurposing for rare diseases

Where multiple links occur between nodes – such as LAM and Lung in this example – these nodes were considered to be more closely linked. Networks were then combined to cover multiple papers, and multiple diseases, building a large network of rare diseases, genes, biological processes, and drugs.

 Picture3 1024x299 Computational approaches may expedite drug repurposing for rare diseases

By arranging the results of a large number of studies – in this case three million – into a single network, links between drugs and diseases that were not previously recognized can be identified. Pathways with fewer steps linking a drug and a disease, and where multiple different pathways linked a drug and a disease, were considered to be particularly plausible candidates for drug repurposing.

To test whether this method led to the identification of new drug-disease pairs, the researchers used the network to identify new therapies for the rare lung disease Sarcoidosis, and new disease targets for the cancer drug Imatinib. They found that the peptides Aviptadil, ɑ-Melanocyte Stimulating Hormone (ɑ-MSH) and C-type Natriuretic Peptide (CNP) were possible candidates to treat Sarcoidosis. Indeed, a Phase II clinical trial in 20 patients reports that Aviptadil is an effective treatment for Sarcoidosis (Prasse et al., 2010), suggesting that ɑ-MSH and CNP may also be effective.

The network also predicted that Imatinib may be an effective treatment for spongiform encephalopathies, such as Creutzfeldt-Jakob disease. Imatinib inhibits the c-Abl tyrosine kinase, which has shown to be dysregulated and lead to neuronal cell death in multiple neurodegenerative disorders (Schlatterer et al., 2011) and Imatinib has been shown to clear mis-folded proteins from prion infected cells (Ertmer et al., 2004).

Together, these results suggest that combined computational linguistics and graph theory is able to identify previously unrecognized drug-disease pairs, which will expedite the repurposing of drugs for new indications.

Drug repurposing is a particularly valuable approach for identifying new treatments for rare and neglected diseases, where there is a high unmet medical need, and a number of rare disease organisations such as Findacure, Cures Within Reach and IRDiRC are actively funding and promoting this research. Indeed, there have been a number of successes in this area, for example Rapamycin has been repurposed as a treatment for Autoimmune Lymphoproliferative Syndrome and thalidomide is now an approved treatment for leprosy, multiple myeloma and bone marrow cancer (Teo et al., 2005).

The number of new therapies being approved for rare diseases is at an all-time high, but with only 133 new therapies approved since 2010, at this rate it will still take around 200 years to develop treatments for all rare diseases. Thus, although computational approaches to drug repurposing are in their infancy, the continued refinement of these approaches to expedite the discovery of drug-disease pairs will be of immense value to the field of rare diseases.


  • Ekins S, Williams AJ, Krasowski MD, & Freundlich JS (2011). In silico repositioning of approved drugs for rare and neglected diseases. Drug discovery today, 16 (7-8), 298-310 PMID: 21376136
  • Ertmer A, Gilch S, Yun SW, Flechsig E, Klebl B, Stein-Gerlach M, Klein MA, & Schätzl HM (2004). The tyrosine kinase inhibitor STI571 induces cellular clearance of PrPSc in prion-infected cells. The Journal of biological chemistry, 279 (40), 41918-27 PMID:15247213
  • Gramatica R, Di Matteo T, Giorgetti S, Barbiani M, Bevec D, & Aste T (2014). Graph theory enables drug repurposing–how a mathematical model can drive the discovery of hidden mechanisms of action. PloS one, 9 (1) PMID: 24416311
  • Liu Z, Fang H, Reagan K, Xu X, Mendrick DL, Slikker W Jr, & Tong W (2013). In silico drug repositioning: what we need to know.Drug discovery today, 18 (3-4), 110-5 PMID: 22935104
  • Prasse A, Zissel G, Lützen N, Schupp J, Schmiedlin R, Gonzalez-Rey E, Rensing-Ehl A, Bacher G, Cavalli V, Bevec D, Delgado M, & Müller-Quernheim J (2010). Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis. American journal of respiratory and critical care medicine, 182 (4), 540-8 PMID: 20442436
  • Schlatterer SD, Acker CM, & Davies P (2011). c-Abl in neurodegenerative disease. Journal of molecular neuroscience : MN, 45(3), 445-52 PMID: 21728062
  • Teo SK, Stirling DI, & Zeldis JB (2005). Thalidomide as a novel therapeutic agent: new uses for an old product. Drug discovery today, 10 (2), 107-14 PMID: 15718159 – the primary online resource for anyone interested in BHD Syndrome.

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Nephron-sparing surgery reduces the risk of cardiovascular events

Radical nephrectomy is generally the preferred method to treat advanced kidney cancers, while partial nephrectomy is performed when the disease is localised, or if the patient has a genetic predisposition to developing kidney tumours. However, a recent study suggests that wherever possible, partial nephrectomy should be used, as the risk of subsequent cardiovascular events is reduced in these patients (Capitanio et al., 2014).

In order to investigate whether the two surgical approaches led to different outcomes, the researchers performed a retrospective review of 1331 patients who had had surgery for kidney cancer at one of four different hospitals between 1987 and 2013. All patients had tumours below 7 cm in diameter, with no metastasis or lymph node involvement; 462 (34.7%) patients had undergone radical nephrectomy, while 869 (65.3%) had undergone nephron sparing surgery.

The researchers analysed these patients’ medical records for pre- and post-surgical glomerular filtration rate, age, BMI, gender, smoking habits, co-morbidities, and cardiovascular events requiring hospitalisation. Cardiovascular events included coronary artery disease, cardiomyopathy, vasculopathy, hypertension, heart failure, dysrhythmias, and cerebrovascular disease. No patients in this study had been diagnosed with any cardiovascular disease prior to their kidney cancer surgery.

Overall, 21.8% of patients had experienced a cardiovascular event within 10 years following surgery. However, when the two groups of patients were analysed separately, 25.9% of the radical nephrectomy patients experienced a cardiovascular event within 10 years following surgery, compared to only 9.9% of the partial nephrectomy patients. Multivariate analysis accounting for the clinical characteristics and cardiovascular profiles of the two groups showed that patients who underwent nephron-sparing surgery were nearly half as likely to develop cardiovascular symptoms after surgery (hazard ratio = 0.57).

Reduced glomerular filtration (GFR) rate post-surgery was also highly correlated with increased risk of cardiovascular events. As radical nephrectomy significantly reduces GFR compared with partial nephrectomy, it is likely that this is responsible for the increased risk of cardiovascular disease in these patients. Interestingly, year of surgery was also correlated with risk of cardiovascular event, suggesting that as surgical techniques have improved over time, the risk of cardiovascular events has fallen. This could also reflect a trend towards increased use of partial nephrectomy to treat localised tumours.

This study suggests that the risk of having a cardiovascular event following kidney surgery is significant, but that the risk is greatly reduced following nephron-sparing surgery. This underscores the importance of improving diagnosis rates, as identifying tumours at an earlier stage will increase the likelihood that a nephron-sparing approach will be curative with respect to the kidney cancer, and will furthermore protect the patient’s cardiovascular health. It additionally provides evidence of the benefit of active surveillance approaches for benign tumours, as removing these tumours is of little clinical benefit to patients, but may increase their risk of developing cardiovascular disease.


  • Capitanio, U., Terrone, C., Antonelli, A., Minervini, A., Volpe, A., Furlan, M., Matloob, R., Regis, F., Fiori, C., Porpiglia, F., Di Trapani, E., Zacchero, M., Serni, S., Salonia, A., Carini, M., Simeone, C., Montorsi, F., & Bertini, R (2014). Nephron-sparing Techniques Independently Decrease the Risk of Cardiovascular Events Relative to Radical Nephrectomy in Patients with a T1a-T1b Renal Mass and Normal Preoperative Renal Function. European Urolology (Epub ahead of print) PMID: 25282367 – the primary online resource for anyone interested in BHD Syndrome.

pf button Nephron sparing surgery reduces the risk of cardiovascular events

Cohort study describes the kidney tumour characteristics of 33 BHD patients

In order to determine the characteristics of renal cell carcinomas (RCC) in BHD patients, Benusiglio et al. (2014) recruited 124 French BHD patients from Hôpital Bicêtre near Paris, and the Edouard Herriot University Hospital in Lyon.

Of the patients recruited, 33 had had kidney cancer. The median age at the diagnosis of the first tumour was 46, with an age range of 20 – 83. Whilst the majority of patients had a solitary tumour at diagnosis, four patients (12%) had two tumours, and nine patients (27%) presented with multifocal disease. Pathology reports were available for all but five patients, and, as expected, the majority of tumours (23/33, or 70%) were of oncocytic or hybrid oncocytic/ choromophobe histology. However, one patient had a papillary RCC, one had an undifferentiated RCC, and 3 patients (9%) had clear cell RCC.

Four patients had metastatic disease at diagnosis. One patient was found to have a lung metastasis 23 years after his initial diagnosis. The metastatic tumour was removed, and the patient showed no sign of cancer relapse upon his death four years later due to an unrelated condition. Another patient received nephrectomy and adjuvant radiotherapy for multiple metastatic retroperitoneal lymph-nodes, and is alive and well seven years later with no signs of disease progression.

Two patients in this cohort received systemic treatment for metastatic disease. One patient presented with multifocal kidney tumours and liver metastases, and disease stability was achieved following three years of systemic treatment with sunitinib, everolimus and temsirolimus. Eight years after ceasing treatment, this patient is still alive and well, and her tumours are stable. Another patient has survived for 5 years following diagnosis, and has received multiple systemic treatments to control slow growing liver and lung metastases.

The survival time following a diagnosis of metastatic renal cancer is usually between 4 months and 2 years (Manola et al., 2011), and all four of these BHD patients have survived with metastatic kidney cancer for more than five years. This suggests that even when BHD renal cancers do metastasise, they are clinically benign compared to more common metastatic renal cancers. Interestingly, mTOR inhibitors achieved long-term disease stability in one patient, which is consistent with the observation that tumours with somatic FLCN mutations respond well to mTOR inhibitors, and suggest that this class of drug may be particularly effective to control metastatic disease in BHD patients.

The results of this study correspond well with previous cohort studies (Schmidt et al., 2005, Toro et al., 2008), and together suggest that roughly 30% of BHD patients are at risk of developing renal cell carcinoma. Although the median age of diagnosis with kidney cancer was 46, the range was 20 – 83 years, suggesting that abdominal screening should commence at a young age – the current recommendation is to commence screening at 20 – 21 years old (Menko et al., 2009, Stamatakis et al., 2013) – and should continue throughout the patient’s lifetime. Furthermore, while the majority of BHD patients who develop RCC will have oncocytic, chromophobe or hybrid tumours, 10% of patients are at risk of developing clear cell RCC, which is more aggressive. Finally, BHD patients who present with metastatic disease seem to have a significantly better prognosis than patients who present with sporadic forms of metastatic RCC.


  • 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
  • Manola J, Royston P, Elson P, McCormack JB, Mazumdar M, Négrier S, Escudier B, Eisen T, Dutcher J, Atkins M, Heng DY, Choueiri TK, Motzer R, Bukowski R, & International Kidney Cancer Working Group (2011). Prognostic model for survival in patients with metastatic renal cell carcinoma: results from the international kidney cancer working group. Clinical cancer research : an official journal of the American Association for Cancer Research, 17 (16), 5443-50 PMID: 21828239
  • Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, Nordenskjöld M, Hansen TV, Solly J, Maher ER, & European BHD Consortium (2009). Birt-Hogg-Dubé syndrome: diagnosis and management. The Lancet. Oncology, 10 (12), 1199-206 PMID: 19959076
  • Schmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ, Turner ML, Choyke PL, Sharma N, Peterson J, Morrison P, Maher ER, Walther MM, Zbar B, & Linehan WM (2005). Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. American journal of human genetics, 76 (6), 1023-33 PMID: 15852235
  • Stamatakis L, Metwalli AR, Middelton LA, & Marston Linehan W (2013). Diagnosis and management of BHD-associated kidney cancer. Familial cancer, 12 (3), 397-402 PMID: 23703644
  • Toro JR, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, Turner M, Choyke P, Merino MJ, Pinto PA, Steinberg SM, Schmidt LS, & Linehan WM (2008). BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. Journal of medical genetics, 45 (6), 321-31 PMID: 18234728 – the primary online resource for anyone interested in BHD Syndrome.

pf button Cohort study describes the kidney tumour characteristics of 33 BHD patients

TSC1 is required for iNKT cell maturation and function

Invariant Natural Killer T (iNKT) cell development is highly regulated, starting at stage 0, where DP thermocytes become committed to the iNKT cell lineage, and ending as fully mature stage 3 iNKT cells, which are capable of illiciting an immune response. iNKT cells are a subtype of T-cells that can recognise bacterial infections, viruses, and even tumours. However, upon repeated exposure, iNKT cells can become anergic and stop responding to stimuli (reviewed by Cianferoni, 2013).

Earlier this year, it was reported that the FLCN interacting protein FNIP1 was required for iNKT cells to complete the stage 2 to 3 transition, that this phenotype was cell autonomous and partially due to mTOR dysregulation (Park et al., 2014). Two studies have found that TSC1, which when mutated causes the related kidney cancer syndrome Tuberous Sclerosis Complex, is required for both iNKT cell development, and mature iNKT cell function.

In order to investigate the role of TSC1 in iNKT cell development, Wu et al. (2014a) specifically deleted TSC1 in murine T-cells using the Cd4Cre allele. They found that although these mice had similar numbers of stage 2 iNKT cells compared with wildtype mice, they had far fewer stage 3 iNKT cells, due to a higher rate of apoptosis in these cells. Therefore, similarly to FNIP1, TSC1 is required to promote the survival of mature stage 3 iNKT cells.

While the overall number of iNKT cells was reduced, a rare subset of iNKT cells which produce IL-17 (iNKT-17 cells) were present in increased numbers in the TSC1fl/fl; Cd4-Cre mice. Expression analysis showed that TSC1 causes cells to preferentially develop into iNKT rather than iNKT-17 cells by promoting the expression of T-bet and inhibiting the expression of RORɣT and ICOS.

Bone marrow transplants into irradiated mice showed using a 1:2.5 mixture of wild-type and TSC1-null bone marrow cells showed stage 1 and 2 iNKT cells were derived from both donor cell types. However, stage 3 iNKT cells were more commonly from wild-type donor cells, indicating that TSC1’s effect on iNKT cell development is cell autonomous. Furthermore, Rapamycin treatment of TSC1fl/fl; Cd4-Cre mice nearly completely reversed the block in iNKT cell development and predominance of iNKT-17 cells, meaning that dysregulated mTOR signaling was responsible for this phenotype. These results are very similar to those seen in FNIP1-null iNKT cells, suggesting that FLCN and TSC1 may co-operate to regulate iNKT cell development.

In a second study from the same team, Wu et al. (2014b) used a Tamoxifen inducible allele to delete TSC1 in mature iNKT cells. They found that, unlike wild-type iNKT cells, TSC1-null iNKT cells did not become anergic upon secondary stimulation with ɑ-galactosylceramide. The expression of the anergy promoting genes PD-1, Egr2, Egr3, Grail and p27kip were all reduced in TSC1-null iNKT cells. This suggests that TSC1 normally promotes an anergic response by activating the expression of these genes. Given the close overlap between TSC1 and FNIP1’s roles in iNKTcell development, it would also be of interest to determine whether FNIP1 or FLCN also regulate iNKT cell anergy.

Anti-cancer vaccines, like the anti-PD1 vaccine, are currently being tested in clinical trials, and preventing T-cell anergy is a significant area of interest to ensure the continued efficacy of vaccinations (Pal et al., 2014). Mice carrying TSC1-null iNKT cells developed fewer tumour nodules than wild-type mice when injected with B16F10 melanoma cells, meaning that reducing the anergic response increased iNKT cells’ ability to target tumours. These results suggest that inhibiting TSC1 in T-cells might prevent them becoming anergic, and so increase the effectiveness of cancer vaccines.

  • Cianferoni A (2014). Invariant Natural Killer T Cells. Antibodies, 3 (1), 16-36 doi: 10.3390/antib3010016
  • 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
  • Pal SK, Hu A, Chang M, & Figlin RA (2014). Programmed death-1 inhibition in renal cell carcinoma: clinical insights and future directions. Clinical advances in hematology & oncology : H&O, 12 (2), 90-9 PMID: 24892254
  • 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
  • Wu J, Yang J, Yang K, Wang H, Gorentla B, Shin J, Qiu Y, Que LG, Foster WM, Xia Z, Chi H, & Zhong XP (2014). iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions. The Journal of clinical investigation, 124 (4), 1685-98 PMID: 24614103
  • Wu J, Shin J, Xie D, Wang H, Gao J, & Zhong XP (2014b). Tuberous sclerosis 1 promotes invariant NKT cell anergy and inhibits invariant NKT cell-mediated antitumor immunity. Journal of immunology (Baltimore, Md. : 1950), 192 (6), 2643-50 PMID: 24532578 – the primary online resource for anyone interested in BHD Syndrome.

pf button TSC1 is required for iNKT cell maturation and function

Somatic mutations in FLCN can cause cancer

The majority of research on FLCN is within the context of BHD syndrome, which is caused by heterozygous germline mutations in the FLCN gene. However, two recent papers have reported that somatic FLCN mutations may be a factor in the development of sporadic tumours.

Sirintrapun et al. (2014) describe the case of a 74 year old man who presented with metastatic renal cancer. Molecular analysis showed that roughly a third of the primary tumour consisted of benign oncocytic cells while the remaining two thirds of the tumour was a high grade oncocytic carcinoma. The patient showed an extended 20 month progression free survival with Temsirolimus treatment.

Genetic and expression profiling revealed that both parts of the tumour had a common origin, indicating that the benign oncocytoma gave rise to the high grade tumour. A number of genomic rearrangements were present in the high grade cells only, including heterozygous loss of 17p, which contains the FLCN gene.

Thus, the authors report a rare case of somatic FLCN deletion contributing to a sporadic case of renal cell carcinoma, and the first known case of a benign oncocytoma transforming to a high grade carcinoma. However, there were additional oncogenic genomic rearrangements present in the high grade oncocytic cells, such as loss of 8p and gain of 8q, suggesting that loss of FLCN was only partly responsible for the disease progression in this patient.

In the second study, Wagle et al. (2014) describe the case of a 57 year old woman with anaplastic thyroid cancer. The patient was enrolled in a phase II clinical trial testing everolimus and had a sustained response for 18 months, at which point her tumour became resistant to treatment. Whole exome sequencing of germline, pretreatment, and resistant tumour DNA revealed that the pretreatment tumour had somatic inactivating mutations in FLCN, TSC2, and TP53, which likely lead to increased mTOR signaling in tumour cells, making the tumour particularly sensitive to treatment with mTOR inhibitiors.

The resistant tumour had developed a missense mutation (mTORF2108L) which prevents everolimus binding to mTOR. In vitro studies show that mTORF2108L is still sensitive to kinase inhibitors, such as Torin1, suggesting that kinase inhibiton may be a suitable follow up treatment for this patient. The authors suggest that sequencing tumour DNA before and during treatment may suggest the most effective treatment regimen for the patient.

These studies contain a number of interesting findings. Firstly, that somatic mutations in the FLCN gene can cause not just kidney cancer, but other tumour types when combined with additional genetic lesions. Indeed, somatic mutations in FLCN have been found in rare cases of sporadic renal cell carcinoma, colorectal cancer, and thyroid oncocytoma (Gad et al., 2007, Kahnoski et al., 2003, Khoo et al., 2003, Pradella et al., 2013). This suggests that BHD is a fundamental disease, and research insights on BHD will yield relevant results for other types of cancer.

Secondly, that FLCN mutations – and other mutations which lead to increased mTOR signaling – may indicate that the tumour will respond well to treatment with mTOR inhibitors, and indeed both patients in these studies had particularly long responses to mTOR inhibitors (20 and 18 months respectively). This is particularly exceptional in the second patient’s case, as the median survival time for anaplastic thyroid cancer is five months.

Thirdly, that a personalised medicine approach – where treatment is based on the underlying metabolic abnormalities present within that tumour – will likely improve cancer survival rates. Additionally, ongoing monitoring of how tumours evolve resistance to treatment will suggest the most effective follow up treatments, even further extending lifespan following a cancer diagnosis.

When considered as a whole, these studies demonstrate the utility of genetic sequencing of tumours to determine how tumours develop and evolve, and suggest that in the future, tumours may be classified and treated according to the mutations they carry, rather than by tumour site.


  • Gad S, Lefèvre SH, Khoo SK, Giraud S, Vieillefond A, Vasiliu V, Ferlicot S, Molinié V, Denoux Y, Thiounn N, Chrétien Y, Méjean A, Zerbib M, Benoît G, Hervé JM, Allègre G, Bressac-de Paillerets B, Teh BT, & Richard S (2007). Mutations in BHD and TP53 genes, but not in HNF1beta gene, in a large series of sporadic chromophobe renal cell carcinoma. British journal of cancer, 96 (2), 336-40 PMID: 17133269
  • Kahnoski K, Khoo SK, Nassif NT, Chen J, Lobo GP, Segelov E, & Teh BT (2003). Alterations of the Birt-Hogg-Dubé gene (BHD) in sporadic colorectal tumours. Journal of medical genetics, 40 (7), 511-5 PMID: 12843323
  • Khoo SK, Kahnoski K, Sugimura J, Petillo D, Chen J, Shockley K, Ludlow J, Knapp R, Giraud S, Richard S, Nordenskjöld M, & Teh BT (2003). Inactivation of BHD in sporadic renal tumors. Cancer research, 63 (15), 4583-7 PMID: 12907635
  • Pradella LM, Lang M, Kurelac I, Mariani E, Guerra F, Zuntini R, Tallini G, MacKay A, Reis-Filho JS, Seri M, Turchetti D, & Gasparre G (2013). Where Birt-Hogg-Dubé meets Cowden syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours. European journal of human genetics : EJHG, 21 (10), 1169-72 PMID: 23386036
  • 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 – the primary online resource for anyone interested in BHD Syndrome.

pf button Somatic mutations in FLCN can cause cancer

BHD lung cysts are not degenerative, but may cause pneumothorax

Although 90% of BHD patients develop lung cysts, there is very little information about the natural history of BHD lung cysts. In order to determine how lung cysts change over time, Johannesma et al. (2014a) compared the results of two CT scans taken at separate intervals, from six BHD patients, five of whom had suffered recurrent pneumothoraces. The time interval between scans ranged from 9 days to 44 months.

One patient developed one new lung cyst in 44 months, and the mean increase in cyst size was 0.4 mm, suggesting that BHD lung cysts do not increase in number or size particularly rapidly. Additionally, if BHD were a progressive degenerative disease, there would be a trend for older patients to develop more pneumothoraces, which has not been reported. Thus, it seems that BHD is not a degenerative disease, with respect to the lung symptoms.

This does raise the question as to when BHD lung cysts develop; there have been five reported cases of children with BHD having pneumothoraces, and FLCN has been shown to be important for alveolar development in mice. Thus, it is possible that lung cysts form during infanthood, childhood or adolescence as lungs are developing, and then remain largely stable during adulthood.

In a separate study, Johannesma et al. (2014b) found that pneumothorax was strongly correlated with the number of lung cysts, but not with their distribution, size or shape. Thus, it seems that the presence of lung cysts somehow causes pneumothoraces.

Johannesma et al. hypothesise that the heterozygous loss of FLCN in the epithelial cells lining cysts means they are more brittle due to increased cell-cell adhesion as reported by Medvetz et al. This causes cysts, and possibly the overlaying visceral pleura, to burst under the mechanical stresses of respiration, allowing air to build up in the pleural space and causing a pneumothorax.

This is similar to the hypothesis suggested by Kumasaka et al. who suggested that reduced cell-cell adhesion, as reported by Nahorski et al, made cyst walls weaker and more likely to burst under mechanical stress, also leading to a build up of air in the pleural space and potentially causing a pneumothorax.

Since the Nahorski and Medvetz studies were published in 2012, FLCN’s function has been shown to be highly cell-specific, which may account for the opposing results of the two studies. However, mouse studies have shown that deletion of FLCN in typeII alveolar lung cells leads to reduced E-cadherin localization at cell membranes, suggesting that lung cysts may indeed have weaker cell-cell contacts.

In either case, it seems that increased numbers of cysts rupturing and causing air to build in the pleural space is a likely mechanism that causes pneumothoraces to develop in BHD patients. Johannesma et al. therefore suggest that eliminating the pleural space by combined pleurectomy and chemical pleurodesis will reduce the recurrence of pneumothoraces in BHD patients. They do however caution that this treatment approach should first be tested in a phase II multicenter clinical trial before becoming the standard of care.


  • Johannesma PC, Houweling AC, van Waesberghe JH, van Moorselaar RJ, Starink TM, Menko FH, & Postmus PE (2014). The pathogenesis of pneumothorax in Birt-Hogg-Dubé syndrome: A hypothesis. Respirology (Carlton, Vic.), 19 (8), 1248-50 PMID: 25302759
  • Johannesma PC,, van Waesberghe JH,, Reinhard R,, Gille J,, van Moorselaar J,, Houweling A,, Starink T,, Menko FH,, & Postmus PE (2014b). Birt-Hogg-Dube Syndrome Patients With And Without Pneumothorax: Findings On Chest CT. American Journal of Respiratory and Critical Care Medicine, 189. [Abstract]
  • 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: histopathological and morphometric analysis of 229 pulmonary cysts from 50 unrelated patients. Histopathology, 65 (1), 100-10 PMID: 24393238
  • Medvetz DA, Khabibullin D, Hariharan V, Ongusaha PP, Goncharova EA, Schlechter T, Darling TN, Hofmann I, Krymskaya VP, Liao JK, Huang H, & Henske EP (2012). Folliculin, the product of the Birt-Hogg-Dube tumor suppressor gene, interacts with the adherens junction protein p0071 to regulate cell-cell adhesion. PloS one, 7 (11) PMID: 23139756
  • Nahorski MS, Seabra L, Straatman-Iwanowska A, Wingenfeld A, Reiman A, Lu X, Klomp JA, Teh BT, Hatzfeld M, Gissen P, & Maher ER (2012). Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis. Human molecular genetics, 21 (24), 5268-79 PMID: 22965878 – the primary online resource for anyone interested in BHD Syndrome.

pf button BHD lung cysts are not degenerative, but may cause pneumothorax

The Amsterdam Patient Charter for Global Kidney Cancer Care

Kidney cancer patients face a number of challenges, such as lack of awareness both by patients and their doctors, difficulty getting a diagnosis, limited access to treatment, inappropriate treatment, lack of information and lack of support. Given that there were an estimated 338,000 new cases of kidney cancer diagnosed in 2012 alone, this is a significant problem.

Following discussions at the International Kidney Cancer Coalition’s (IKCC) 4th Expanding Circles conference in Amersterdam earlier this year, the IKCC have published the Amsterdam Patient Charter for Global Kidney Cancer Care (Giles et al., 2014) which aims to address these challenges. The Charter outlines the rights of kidney cancer patients worldwide, and consists of ten points, which you can read here, and can be broadly split into three categories: clinical care, support, and information and empowerment.

Regarding clinical care, the charter states that patients should expect timely investigation, accurate diagnosis, access to the best available evidence-based therapies and treatment from doctors with specialist knowledge about kidney cancer. These measures will all lead to improved health outcomes for people with kidney cancer.

It was recently reported that doctors consistently underestimated the number of kidney cancer patients who became depressed after their diagnosis. The Amsterdam Patient Charter recommends that patients should be offered regular follow-up care, including psychosocial support, and given information about patient support and relevant advocacy organisations. Additionally, as kidney cancer can have long term health effects, patients should be given survivorship support, and recommendations about how to preserve health. These measures will help patients to cope with their illness and treatment and will allow patients to return to their normal lives.

Finally, patients should be offered accessible information specifically written for patients about all aspects of their disease course, including treatment, clinical trials, pain control, palliative care, survivorship and available support. Furthermore, patients should be given access to their medical records, and encouraged to take an active role in any decision-making regarding their treatment. Having better knowledge about their disease, and being given the opportunity to participate in the decision-making process, will empower patients to feel they have control over their care.

Of particular interest to BHD patients, point 10 of the charter highlights the fact that 10% of kidney cancer cases are caused by hereditary syndromes, and that these cases must be managed differently to sporadic cases. As these patients carry a genetic predisposition to develop kidney cancer, tumours must be treated more conservatively by partial rather than total nephrectomy, and patients require specialised care throughout their lifetime.

This initiative comes in same year as European Cancer Patients’ Bill of Rights, which aims to improve health outcomes by ensuring every European cancer patient has access to the best care, evidence-based treatment, and information. Although it is unclear how these charters will be enforced, their existence demonstrates the commitment of doctors, patient advocates, researchers and policy makers to improving the experience of cancer patients in Europe and kidney cancer patients worldwide.


  • Giles RH, Maskens D, & the International Kidney Cancer Coalition (2014). Amsterdam Patient Charter for Global Kidney Cancer Care. European urology PMID: 25257033 – the primary online resource for anyone interested in BHD Syndrome.

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