A shower of second hit mutations causes bilateral, multifocal kidney cancer in TSC patients

Tuberous sclerosis complex (TSC) is caused by autosomal dominant inactivating mutations in either the TSC1 or TSC2 genes, and patients are predisposed to developing tumours in the brain, eyes, heart, skin, lungs and kidneys throughout their lifetime. While more than 80% of TSC patients develop benign renal angiomyolipoma, only 3% of TSC patients develop renal cell carcinoma (Yang et al., 2014).

Tyburczy et al., (2014) describe two TSC patients who presented with bilateral multifocal renal cell carcinoma.

The first patient received a left nephrectomy to remove 12 tumours at the age of 24. Three years later, a right nephrectomy was required to remove three tumours. Histological analysis showed all tumours to be of TSC-associated papillary renal cell carcinoma (RCC) (Yang et al., 2014).

Fresh frozen tissue was available from four left and one right kidney tumour. Direct sequencing and microsatellite marker analysis showed loss of heterozygosity (LOH) at the TSC2 allele in one tumour sample, but not in the other four tumours. Targeted next generation sequencing found different second hit somatic TSC2 mutations in each of the other four tumours: two nonsense, one frameshift and one missense mutation. Whole exome sequencing of DNA from all five tumours showed an average of four somatic mutations in other genes in each tumour, and no gene was mutated in more than one sample. Furthermore, no copy number changes were observed in any tumour. This suggests that biallelic inactivation of TSC2 is the driving tumorigenic mutation in all five tumours.

The second patient was found to have bilateral, multifocal tumours, and received partial nephrectomy of both kidneys at the age of 36. All tumours showed the same TSC-associated papillary RCC histology. Analysis of three tumours showed no evidence of LOH at the TSC2 allele. Only one tumour sample yielded sufficient DNA for sequencing analysis, and showed a somatic splicing mutation in TSC2, again suggesting that somatic second hits in TSC2 are driving tumorigenesis in this patient.

Both patients carried the same missense R905Q TSC2 mutation, which is associated with a milder presentation of TSC (Jansen et al., 2006). As this mutation is present in fewer than 1% of TSC patients, and only 3% of TSC patients develop RCC, it seems likely this this mutation may predispose patients to developing RCC. Indeed, in a cohort of 19 TSC patients who developed RCC, germline sequencing data was available for three patients who also developed TSC-associated papillary RCC. While none carried the R905Q mutation, all three had non-truncating TSC2 mutations – two missense and one in-frame deletion. This suggests that patients with non-truncating mutations may be at a higher risk of developing RCC (Yang et al., 2014).

Tyburczy et al. calculate the likelikhood of the first patient developing 15 tumours through 15 independent second hit events to be 1 in 3.6 trillion. This suggests that all tumours arose following a single event, which led to a shower of second hit TSC2 mutations occuring in these patients’ kidney tissue. However, the disease mechanism that leads to multiple second hit mutations in in a single gene is currently unknown.

 

  • Jansen AC, Sancak O, D’Agostino MD, Badhwar A, Roberts P, Gobbi G, Wilkinson R, Melanson D, Tampieri D, Koenekoop R, Gans M, Maat-Kievit A, Goedbloed M, van den Ouweland AM, Nellist M, Pandolfo M, McQueen M, Sims K, Thiele EA, Dubeau F, Andermann F, Kwiatkowski DJ, Halley DJ, & Andermann E (2006). Unusually mild tuberous sclerosis phenotype is associated with TSC2 R905Q mutation. Ann Neurol, 60 (5), 528-39 PMID: 17120248
  • Tyburczy ME, Jozwiak S, Malinowska IA, Chekaluk Y, Pugh TJ, Wu CL, Nussbaum RL, Seepo S, Dzik T, Kotulska K, & Kwiatkowski DJ (2014). A shower of second hit events as the cause of multifocal renal cell carcinoma in Tuberous Sclerosis Complex. Hum Mol Genet PMID: 25432535
  • Yang P, Cornejo KM, Sadow PM, Cheng L, Wang M, Xiao Y, Jiang Z, Oliva E, Jozwiak S, Nussbaum RL, Feldman AS, Paul E, Thiele EA, Yu JJ, Henske EP, Kwiatkowski DJ, Young RH, & Wu CL (2014). Renal cell carcinoma in tuberous sclerosis complex. Am J Surg Pathol, 38 (7), 895-909. PMID: 24832166

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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Providing written information significantly improves parents’ understanding of TSC

Last week, we launched the new patient information pages on the BHD Foundation website. The information has been rewritten with the principles of health literacy in mind, and we hope these will be of greater use to patients and their families. This week’s blog discusses a study which demonstrates the value of providing well-written patient information.

Tuberous Sclerosis Complex (TSC) is a paediatric genetic syndrome which causes tumours to form in the brain, eyes, heart, skin, lungs and kidneys. There is no cure for TSC, but correct management of the individual symptoms can greatly improve health outcomes. Thus, educating care givers – usually the child’s parents – can improve patients’ quality of life.

Samia et al. (2014) tested whether providing parents with written information in addition to the information given in person at the TSC clinic in Cape Town, South Africa, improved parents’ understanding of TSC. 21 parents took part in the study, their baseline understanding of TSC was determined, and parents were split into two groups at random. The first group received a written leaflet about TSC to take home after their child’s appointment, while the second group did not. Parents’ knowledge of TSC was assessed 3 months later at their child’s next clinic appointment. Leaflets were based on information available on the TS Alliance website, and translated into both Xhosa and Afrikaans.

The study found that parents’ understanding of TSC increased by 20% in the group who received the written leaflet, compared with only 3% in the group who did not. The difference in knowledge was particularly striking in those parents who had completed between 8 and 11 years of education. The level of knowledge improved less in those parents who had over 11 years of education, suggesting that their baseline level of understanding was already high.

However, the study also found that written information was not useful to those parents who had not completed at least 8 years of education, and should be supplemented with verbal counseling. These appointments should be in a more relaxed setting, as previous studies have shown that in the formal setting of a doctor’s appointment, patient retention of information is low.

In this study, the majority of caregivers who took part in the study were female (18/21), and for most the clinic was their primary source of information about TSC. However, there are countries where women do not receive the same level of education as men, but are still likely to be the main caregiver of a disabled child. In these cases, health information providers will need to predominantly cater for a low literacy audience.

Additionally, in the UK, the internet is the primary source of health information for 87% of people, meaning that information providers should predominantly produce online content, and concentrate less on developing hard copy pamphlets to distribute at clinics. Thus, information providers need to understand their audience and have a flexible approach. This is especially important for those writing rare disease information, where fewer information resources are available and information providers are more likely to be generating information that is used internationally.

The link between improved health literacy and health outcomes is well-documented (Berkman et al., 2011): greater understanding of a disease leads people to seek diagnosis earlier and to greater compliance to treatment regimens. In turn this leads to improved health outcomes and reduced healthcare costs. Therefore, providing patients and caregivers with the right information, at the right time, and in the right format is an issue of public health.

 

  • Berkman ND, Sheridan SL, Donahue KE, Halpern DJ, & Crotty K (2011). Low health literacy and health outcomes: an updated systematic review. Ann Intern Med, 155 (2), 97-107. PMID: 21768583
  • Samia P, Donald KA, Schlegel B, & Wilmshurst JM (2014). Parental Understanding of Tuberous Sclerosis Complex. J Child Neurol. PMID: 25414235

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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Introducing the new BHD patient information pages

Like many rare diseases, there is no cure for BHD. However, appropriate management of symptoms – particularly kidney cancer – can vastly reduce the likelihood of early death due to the disease (Menko et al., 2009, Stamatakis et al., 2013). Therefore, providing BHD patients with clear, easy to understand information can help patients manage their condition and improve their quality of life.

Last year we wrote about how learning about health literacy helped us develop our Introductory Pamphlets for newly diagnosed patients. Whilst doing this project, we realised that some of the patient information on the website was quite technical and could be improved. Today we are pleased to launch the new patient information pages. These have been updated to include new information, and rewritten with the principles of health literacy in mind.

The new patient pages are split into ten sections: What is BHD; a Genetics overview; information about the skin, lung, kidney and other symptoms of BHD; practical considerations; the Science of BHD; FAQs; and Glossary.

What is BHD, simply provides a brief overview of BHD. The “Genetics overview” describes the genetics of BHD; suggests who should be tested for BHD, and why you should consider genetic testing; provides information about the genetic test itself and getting the results; and discusses the next steps are if you do have BHD, including information about how to find a doctor.

Previously, medical information about BHD was split into two sections: symptoms, and treatment & diagnosis. Now, this information is split into the different organs affected by BHD: skin, lung, kidney and other symptoms. For the skin, lung and kidney sections, each has its own introduction, followed by information about the symptoms, diagnosis, treatment options and differential diagnosis.

The “Practical considerations” section has remained largely the same. However, we have added three new resources to “Telling others about BHD”. The Medical Education Kit links to three important papers written by BHD experts, describing the best treatment regimens for patients (Gupta et al., 2013, Menko et al., 2009, Stamatakis et al., 2013). We recommend that patients print out copies of these papers to give to their doctors. This allows patients to educate their doctors about BHD and the best methods of treating patients. We have also written a lay summary of each paper so that patients are aware of the results and recommendations outlined in each.

To help patients tell their families about BHD, we have written a BHD Family Letter, which can be personalised to fit each patient’s circumstances. We have also reinstated the BHD Medicard, which can be folded into the size of a credit card, meaning that patients can easily carry round a handy list of their symptoms and treatments at all times.

There are three brand new sections. Firstly, we have added an FAQs section, which lists the answers to questions we are often asked about BHD. We have also added a glossary of terms, which spells out the more difficult or unfamiliar terms phonetically. And finally, we have written a brief description of the science of BHD specifically for patients. This section does not provide information that is directly relevant to patients’ health or care, but provides an insight into the underlying biology of the disease.

We hope that patients find the new pages informative and are better able to understand and manage their condition as a result. If you would like give any feedback on the new pages, you can email us at contact@BHDSyndrome.org, or fill out our online feedback form.

  • Gupta N, Seyama K, & McCormack FX (2013). Pulmonary manifestations of Birt-Hogg-Dubé syndrome. Familial cancer, 12 (3), 387-96 PMID: 23715758
  • 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
  • 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

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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The natural history of angiomyolipoma in cases of sporadic LAM

Lymphangioleiomyomatosis (LAM) is a cystic lung disease that predominantly affects women. Roughly 90% of cases are sporadic and are caused by somatic mutation of the TSC2 gene, but some patients develop LAM as part of the syndrome Tuberous Sclerosis Complex (TSC), which is caused by germline mutations either TSC1 or TSC2.

Angiomyolipoma (AML) is a type of kidney tumour that develops in nearly 100% of patients with TSC, and 50% of patients with sporadic LAM. AML are typically benign, but if untreated, larger tumours can haemorrhage and require the patient to undergo a nephrectomy. While the natural history of AML is known for TSC patients, it has not been systematically studied in LAM patients, and there are no official clinical recommendations of how to monitor and treat AML in sporadic LAM patients.

Yeoh et al. (2014) recently published a natural history study on a cohort of 107 sporadic LAM patients recruited via the National Centre for LAM in Nottingham, UK. Of these patients, 53 (50%) had had at least 1 AML in their lifetime and the average age of AML diagnosis was 39.1. Ten patients were diagnosed with AML up to 11 years before they were diagnosed with LAM, ten patients were diagnosed with both at the same time, and the remaining patients were diagnosed with AML up to 38 years after their LAM diagnosis. This suggests that sporadic LAM patients are at risk of developing AML throughout their entire lifetime.

Presence of AML was not linked to the severity of the pulmonary symptoms of LAM in these patients. AMLs in sporadic LAM patients were generally smaller, less likely to be bilateral, and the time from diagnosis to renal event – such as haemorrhage or surgical intervention – was 34 years, compared with 25 years in TSC patients. However, there was no difference in the incidence of haemorrhage or the need for medical intervention between this cohort and TSC patients. This suggests that AML in sporadic LAM patients should be managed in a similar fashion to AML in TSC patients.

The authors recommend that abdominal MRI should be performed every 1 to 3 years throughout the lifetime of sporadic LAM patients, and surgical intervention should occur when tumours reach 3 cm, as patients with larger tumours are at significant risk of haemorrhaging. All patients should have an abdominal MRI scan when they are diagnosed with LAM to assess whether they have any AMLs. Patients with tumours smaller than 1 cm in diameter should have follow up scans every two years, patients with tumours between 1-2cm in diameter should be screened annually, and patients with tumours over 3 cm should either have follow up scans after 6 months, or should be referred for intervention.

The authors note that this study only takes tumour size into account and suggest that contrast CT or MRI could be used to detect the vasculature of AML tumours, which may allow patients to be stratified into high risk and low risk groups that are managed differently. Indeed, there were 11 patients in this cohort who underwent nephrectomy to treat AML haemorrhage, and the average age of these patients at the time of surgery was 23. This is significantly younger than the average age of AML diagnosis of the cohort as a whole, which was 39.1, and suggests that these 11 patients did have a more aggressive form of AML.

  • Yeoh ZW, Navaratnam V, Bhatt R, McCafferty I, Hubbard RB, & Johnson SR (2014). Natural history of angiomyolipoma in lymphangioleiomyomatosis: implications for screening and surveillance. Orphanet journal of rare diseases, 9 PMID: 25277108

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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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

www.bhdsyndrome.org – 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

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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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

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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