Highlights from the 4th International Kidney Cancer Coalition Conference

In the first week of April, the International Kidney Cancer Coalition (IKCC) held its 4th Expanding Circles conference in Amsterdam. The meeting brought together kidney cancer patient advocates from all over the world to discuss current and future treatments, best practices and how to improve the outlook for kidney cancer patients globally.

Professor Peter Boyle, author of The State of Oncology, presented data on the global burden of cancer and showed that 5 year survival rates for a number of cancers have increased. For example, prostate cancer 5 year survival rates have increased ten-fold from 8% in the early 1940s to 82% in 2007 (De Angelis et al., 2014). Professor Boyle highlighted the fact that increased survival is not due to a single magic bullet, but to the accumulation of small, incremental improvements over the past 60 years.

Professor Anne Merriman, a nominee for the 2014 Nobel Peace Prize, spoke about her work leading Hospice Africa (Uganda). Before the 1990s, access to pain medicines was difficult in Africa, rendering palliative care impossible. The Merriman Model means morphine can be made up near the patient and taken orally, allowing cancer patients to have a painless, dignified death at home surrounded by their loved ones.

Dr Daniel Heng presented an update on targeted therapies. In the last seven years, five VEGF inhibitors (Sunitinib, Sorafenib, Pazopanib, Axitinib and Bevacizumab) and two mTOR inhibitors (Temsirolimus and Everolimus) have been approved to treat kidney cancer. Further systematic trials are required to determine the optimal order of targeted treatments, particularly for second and third lines of therapy. However, retrospective analysis of data from the International metastatic Renal Cell Carcinoma (mRCC) Database Consortium (IMDC) shows that patients who receive more lines of targeted therapy live longer (Ko et al., 2014) and that targeted therapy leads to doubled overall survival than interferon therapy, demonstrating that the prognosis for patients with mRCC is improving.

Dr Axel Bex presented the surgical perspective of how kidney cancer treatment is changing as surgeons tend towards ablative and nephron sparing surgeries. Neoadjuvant therapy, where pre-operative targeted therapy is used to downsize or downgrade a tumour in order to improve surgical outcomes, was also discussed. Early data from a trial testing the efficacy of neoadjuvant Axitinib in locally advanced RCC indicate that tumour volume does reduce and that this might be an effective approach.

Additionally, Dr Eric Jonasch introduced the audience to the hereditary kidney cancer syndromes, including Birt-Hogg-Dubé syndrome; Dr Marry van den Heuvel-Eibrink summarised the symptoms, causes and treatment options for paediatric kidney cancers, including Wilms’ Tumour; and Professor Kerstin Junker presented her work on identifying prognostic biomarkers for kidney cancer, including her team’s discoveries that certain genetic duplications or losses and miRNA expression profiles correlate with increased metastasis (Heinzelmann et al., 2014, Sanjmyatav et al., 2011).

For many cancers, the UK has higher cancer mortality rates than the European average (De Angelis et al., 2014), which is thought to be partly due to patients from lower socioeconomic groups waiting longer to seek medical advice. James Brandon, from Public Health England spoke about the “Be Clear on Cancer” campaign to raise awareness about kidney and bladder cancer in the UK. Two television adverts were produced, one for men and one for women, along with poster and radio campaigns, urging people to visit their GP urgently if they notice blood in their urine. Tracking results from an earlier equivalent campaign for colorectal cancer showed that more people visited their GP and the number of appropriate referrals increased.

On the last day, 5 speakers from patient organisations shared information and experiences working on specific projects during the “Sharing Best Practices” Session. Denis Brezillion, from ARTuR in France, informed the audience how his volunteer-led organisation run a conference for 200 patients every year in Paris, while Berit Eberhardt, from Das Lebenshaus in Germany,  urged all patient advocates to “beg, borrow and steal” good ideas from other organisations, and to recombine them to make better patient literature. Following on this theme, Lizzie Perdeaux from the Myrovlytis Trust/ BHD Foundation presented information on health literacy and how this helped us design the new Introductory BHD Pamphlets. Luciana Holtz of Instituto Oncoguia described how, although heart disease is the biggest killer in Brazil, 59% of Brazilians think that cancer is the most common cause of death. As a result, many fear cancer and do not adhere to screening programmes. In 2013, Luciana’s team ran a successful awareness campaign on social media to spread the message that “cancer is no longer a death sentence, but you have to do your part.”

Finally, Deb Maskens from Kidney Cancer Canada introduced the Cancertainty For All campaign. In 6 of Canada’s 10 provinces, intravenous cancer treatment starts quickly and is free. However, the route to access oral medication is laborious and time-consuming, and patients have to cover much of the cost themselves. Kidney Cancer Canada formed a coalition of over 30 Canadian cancer charities and produced an infographic and video to raise public awareness of this issue.

The conference was a wonderful opportunity to meet patient advocates from all over the world, and to hear about some of the inspiring projects helping kidney cancer patients today. The outlook for kidney cancer patients is one of great hope, with targeted therapies already having doubled survival times, and with several promising treatments on the horizon, such as dendritic cell immunotherapy, anti-PD1 therapy and Cabozantinib.

  • De Angelis R, Sant M, Coleman MP, Francisci S, Baili P, Pierannunzio D, Trama A, Visser O, Brenner H, Ardanaz E, Bielska-Lasota M, Engholm G, Nennecke A, Siesling S, Berrino F, Capocaccia R, & EUROCARE-5 Working Group (2014). Cancer survival in Europe 1999-2007 by country and age: results of EUROCARE–5-a population-based study. The lancet oncology, 15 (1), 23-34 PMID: 24314615
  • Heinzelmann J, Unrein A, Wickmann U, Baumgart S, Stapf M, Szendroi A, Grimm MO, Gajda MR, Wunderlich H, & Junker K (2014). MicroRNAs with prognostic potential for metastasis in clear cell renal cell carcinoma: a comparison of primary tumors and distant metastases. Annals of surgical oncology, 21 (3), 1046-54 PMID: 24242678
  • Ko JJ, Choueiri TK, Rini BI, Lee JL, Kroeger N, Srinivas S, Harshman LC, Knox JJ, Bjarnason GA, Mackenzie MJ, Wood L, Vaishampayan UN, Agarwal N, Pal SK, Tan MH, Rha SY, Yuasa T, Donskov F, Bamias A, & Heng DY (2014). First-, second-, third-line therapy for mRCC: benchmarks for trial design from the IMDC. British journal of cancer PMID: 24691425
  • Sanjmyatav J, Junker K, Matthes S, Muehr M, Sava D, Sternal M, Wessendorf S, Kreuz M, Gajda M, Wunderlich H, & Schwaenen C (2011). Identification of genomic alterations associated with metastasis and cancer specific survival in clear cell renal cell carcinoma. The Journal of urology, 186 (5), 2078-83 PMID: 21944119

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

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Why are patient registries important?

How many people have BHD? Who will develop which symptoms, when?  How severe will they be?

These are very straightforward questions, but there is not sufficient information to accurately answer them at the moment. This is where patient registries are so powerful, particularly for rare diseases.

A patient registry simply stores an individual’s personal information and their medical history, and registries are usually disease-specific. This allows researchers to more accurately estimate both the prevalence and incidence of the disease, and to determine their natural history, providing answers to the above questions. Once this information is known, it can be used to give more accurate advice to patients, and to improve care pathways, which can lead to improved care and life expectancy, even in the absence of a cure.

Registries can be used prospectively to quickly identify patients eligible for a clinical trial, or retrospectively to analyse the effectiveness of an intervention. For example, retrospective analysis of the California Cancer Registry showed that while overall incidence of colorectal cancer declined between 1988 and 2007, incidence increased in Korean communities (Giddings et al., 2012). This correlated with data showing that this group were less likely to attend screening, enabling California’s Comprehensive Cancer Control Program to develop educational programmes specifically for Korean communities about the importance of colorectal cancer prevention and screening.

International co-operation is vital to get a sufficient amount of information in order for rare disease patient registries to realise their full potential. However, although there are currently roughly 640 rare disease registries in Europe, the minority are pan-European or global (Aymé and Rodwell, 2014).

On 21st March, the Cancer in our Genes International Patient Databank (CGIP) patient registry for Birt-Hogg-Dubé Syndrome (BHD), Von Hippel Lindau Syndrome (VHL), Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) and Succinate Dehydrogenase (SDH) patients was launched. The registry is an initiative of the VHL Alliance, and has been part funded by the Myrovlytis Trust, the parent charity of the BHD Foundation.

The CGIP records information on patients’ specific mutation, symptoms, previous treatments, ethnicity, lifestyle and mental health. By recording such a wide range of information, the registry will provide insight on the epidemiology or any genotype-phenotype correlations in these diseases; whether certain treatments have better outcomes; how lifestyle affects disease progression; and how mental health is affected. Of particular interest for BHD patients and researchers, if enough BHD patients take part, the registry may shed light on whether colonic polyps or parotid tumours are symptoms of BHD.

The information collected in this registry will help researchers and clinicians better characterise BHD, VHL, HLRCC and SDHB, and will enable them to give more complete advice and optimised care to patients.

The CGIP Databank is maintained on a secure server, and the VHLA will only allow authorised third parties – namely researchers and clinicians – access to an anonymised dataset. This is standard practise to ensure the privacy of registrants.

If you have BHD, VHL, HLRCC or SDHB, and would like to find out more information, please click on one of the following links, or on the green button below:

registry button e1395412258368 300x79 Why are patient registries important?

  • Aymé S, & Rodwell C (2014). The European Union Committee of Experts on Rare Diseases: three productive years at the service of the rare disease community.Orphanet journal of rare diseases, 9 (1) PMID: 24580800
  • Giddings BH, Kwong SL, Parikh-Patel A, Bates JH, & Snipes KP (2012). Going against the tide: increasing incidence of colorectal cancer among Koreans, Filipinos, and South Asians in California, 1988-2007. Cancer causes & control : CCC, 23 (5), 691-702 PMID: 22460700

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

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FLCN may act as a molecular switch

Chromosome translocations involving the transcription factor TFE3, leading to its overexpression, cause roughly 15% of renal cell carcinomas in patients under 45 years of age (Kuroda et al., 2012). TFE3 is constitutively activated in FLCN-null cells (Hong et al., 2010), indicating that FLCN may regulate TFE3. While investigating the role of TFE3 in lysosome homeostasis and autophagy, Martina et al. (2014) demonstrated that although FLCN does not directly interact with TFE3, it controls TFE3 via mTORC1 signalling.

Martina et al. (2014) show that under amino acid sufficiency, active GTP-bound Rag proteins recruit TFE3 to the lysosome, where it is phosphorylated at S311 by mTORC1 and remains in the cytoplasm in ARPE-19, HeLa and HepG2 cells. Under amino acid starvation, the Rag proteins and mTORC1 are no longer active, and unphosphorylated TFE3 translocates to the nucleus where it activates the transcription of target genes, including lysosome and autophagy genes. Thus, under starvation conditions, autophagy is initiated by TFE3.

The authors found that FLCN was required for correct phosphorylation of TFE3 by mTORC1, with FLCN knock down leading to aberrant autophagy in cells during nutrient sufficiency. It has previously been shown by two independent groups that the Rag proteins recruit FLCN to lysosomes during amino acid starvation, where it activates mTORC1 and dissociates from the lysosome once amino acid levels are restored. Martina et al. also observed this pattern of activity. Additionally, TFE3 overexpression led to increased mRNA levels of FLCN, FNIP1 and FNIP2, suggesting that TFE3 autoregulates its activity via FLCN. Taken together, FLCN seems to act as a molecular switch, making starved cells poised to quickly reactivate mTOR signalling and inhibit TFE3 induced autophagy as soon as nutrients become available.

This corresponds well with previous studies that have suggested that FLCN inhibits autophagy, which are summarised here. Additionally, a number of studies either directly or indirectly suggest that FLCN may act as a molecular switch to regulate cell homeostasis or differentiation in response to external stimuli.

In exactly the same way that FLCN regulates TFE3 localisation via mTORC1 in upon amino acid restimulation, FLCN also regulates TFEB – another transcription factor from the same family as TFE3 (Petit et al., 2013).  Furthermore, Betschinger et al. (2013) reported that the FLCN-FNIP1-FNIP2 complex controls exit from pluripotency by precluding TFE3 from the nucleus in response to differentiation signals.

Martina et al. show that elevated TFE3 activity led to increased exocytosis of lysosomes, and an increase in the acidity of growth medium. Under hypoxia, VHL conserves ATP by causing cells to acidify their environment and inhibiting rRNA synthesis. FLCN also inhibits rRNA synthesis and is known to be an effector protein of VHL under certain circumstances. It is therefore possible that under hypoxia, FLCN also acts to conserve cellular energy by inhibiting rRNA synthesis and activating acidosis by allowing TFE3 to increase lysosome exocytosis.

Finally, loss of FNIP1 leads to a block in B-cell differentiation in mice, while TFE3-null B-cells show impaired activation (Merrell et al., 1997), suggesting that this pathway might be responsible for correct B-cell maturation during development or following exposure to an antigen.

Precisely how FLCN is able to act as a molecular switch is currently unknown. However, the alternative splicing of FNIP1 is evolutionarily conserved and happens in response to differentiation signals during mesoderm differentiation, making this a viable and intriguing possibility.

 

  • Betschinger J, Nichols J, Dietmann S, Corrin PD, Paddison PJ, & Smith A (2013). Exit from pluripotency is gated by intracellular redistribution of the bHLH transcription factor Tfe3. Cell, 153 (2), 335-47 PMID: 23582324
  • Kuroda N, Mikami S, Pan CC, Cohen RJ, Hes O, Michal M, Nagashima Y, Tanaka Y, Inoue K, Shuin T, & Lee GH (2012). Review of renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions with focus on pathobiological aspect. Histology and histopathology, 27 (2), 133-40 PMID: 22207547
  • Martina JA, Diab HI, Lishu L, Jeong-A L, Patange S, Raben N, & Puertollano R (2014). The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris. Science signaling, 7 (309) PMID: 24448649
  • Merrell K, Wells S, Henderson A, Gorman J, Alt F, Stall A, & Calame K (1997). The absence of the transcription activator TFE3 impairs activation of B cells in vivo. Molecular and cellular biology, 17 (6), 3335-44 PMID: 9154832
  • Petit CS, Roczniak-Ferguson A, & Ferguson SM (2013). Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. The Journal of cell biology, 202 (7), 1107-22 PMID: 24081491

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

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Rare diseases are fundamental to understanding common diseases

Research has historically concentrated on more common diseases, seeking to benefit the many rather than the few, and as a result rare diseases have often been overlooked. However, a growing body of evidence shows that rare disease research can yield important insight into more common conditions. Additionally, rare diseases are often more extreme and have a more straightforward aetiology than their common counterparts, and therefore provide models of disease that are easier to study.

Findacure, a new charity promoting the research and development of treatments for rare diseases, thinks that terminology – “rare”, “orphan”, “neglected” – also explains why this group of diseases has been overlooked for so long. Thus, they are seeking to re-frame rare diseases as “fundamental diseases”, because they are fundamental to understanding more common diseases. Specifically, Findacure’s definition of a fundamental disease is one that has a genetic cause, is rare and largely neglected, and is likely to be amenable to a therapy. To raise awareness of this concept in the scientific community, Findacure recently held their First Scientific Workshop on Fundamental Diseases at Sidney Sussex College in Cambridge.

Professor Eamonn Maher, from the University of Cambridge, presented his work on the rare genetic kidney cancer predisposition syndrome Von Hippel-Lindau (VHL), and how this has benefited patients with more common kidney cancers. VHL is the most commonly mutated gene in sporadic kidney cancers, accounting for around 74% of clear cell RCCs (Banks et al., 2006). Research on VHL showed that under normoxia, the VHL protein marks HIF1a and 2a for proteolysis, thus preventing angiogenesis, and correlates with the observation that VHL-null kidney tumours are highly vascular (Maxwell et al., 1999). These findings suggested that these cancers might respond well to anti-angiogenic drugs, specifically Tyrosine Kinase inhibitors, which are now a commonly used therapy for kidney cancer.

Professor Timothy Cox, from the University of Cambridge, spoke about the historical link between rare and common diseases. One interesting example he used was that of Familial Hypercholesterolemia (FH), which is caused by mutations in the LDL Receptor gene. Biallelic mutations cause the most severe form of disease, and heart attacks have been reported in children as young as 2 years old (Carlson, 2010). Statins were developed as a cure for FH, and are now the most commonly prescribed drug in the UK for high cholesterol, with Pfizer reporting Lipitor sales revenues of $12.4 billion in 2008.

Professor James Gallagher, from the University of Liverpool, explained how his work on the rare disease Alkaptonuria (AKU) has yielded insight into normal ageing and osteoarthritis, which affects 1 in 3 people over the age of 45. AKU is caused by recessive mutations in the HGD gene, which causes an early onset and severe form of arthritis. Through his work with AKU patients and mouse models, Professor Gallagher has shown that collagen fibres become more vulnerable with age due to general wear and tear (Chow et al., 2011), and that this ageing process starts early, well before any macroscopic signs of ageing are visible. Additionally, he has shown that joint degeneration begins in calcified cartilage, and that trabecular excrescences and sub-chondrial protrusions are characteristic of both damaged AKU joints and arthritic joints (Taylor et al., 2011, Taylor et al., 2012).

Dr Anil Mehta spoke about how research on a specific Cystic Fibrosis mutation has revealed information about the selection forces humans have been subject to during evolution. Cystic Fibrosis is a life-threatening and disabling rare disease caused by biallelic mutations in the CTFR gene. 70% of Cystic Fibrosis cases are caused by biallelic inheritance of the ΔF508 mutation (Riordan, 2005). ΔF508 is a founder mutation that arose in Europe around 50,000 years ago and now is now common in the UK population, with 1 in 60 people estimated to be carriers (Morral et al., 1994). Research from Professor Mehta’s lab has found that the peptide sequence surrounding this mutation is found in the IgG binding domain in many pox viruses (Treharne et al., 2009). Thus, having a single copy of ΔF508 ablates CFTR’s binding site and confers resistance to pox, which may explain the prevalence of this allele in European populations.

Thus research on fundamental diseases can yield important insight into the pathogenesis of more common diseases, lead to the development of block-buster drugs, and can even explain how certain genetic mutations have become so common in today’s population. By working with patient groups, academia and the Pharmaceutical industry, Findacure aims to build a movement for fundamental diseases that drives research, drug development and health policy reform.

  • Banks RE, Tirukonda P, Taylor C, Hornigold N, Astuti D, Cohen D, Maher ER, Stanley AJ, Harnden P, Joyce A, Knowles M, & Selby PJ (2006). Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer. Cancer research, 66 (4), 2000-11 PMID: 16488999
  • Carlson R (2010). Familial hypercholesterolemia captures gene test controversies. Biotechnology healthcare, 7 (1), 8-9 PMID: 22478804
  • Chow WY, Taylor AM, Reid DG, Gallagher JA, & Duer MJ (2011). Collagen atomic scale molecular disorder in ochronotic cartilage from an alkaptonuria patient, observed by solid state NMR. Journal of inherited metabolic disease, 34 (6), 1137-40 PMID: 21735270
  • Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, & Ratcliffe PJ (1999). The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature, 399 (6733), 271-5 PMID: 10353251
  • Morral N, Bertranpetit J, Estivill X, Nunes V, Casals T, Giménez J, Reis A, Varon-Mateeva R, Macek M Jr, & Kalaydjieva L (1994). The origin of the major cystic fibrosis mutation (delta F508) in European populations. Nature genetics, 7 (2), 169-75 PMID: 7920636
  • Riordan JR (2005). Assembly of functional CFTR chloride channels. Annual review of physiology, 67, 701-18 PMID: 15709975
  • Taylor AM, Boyde A, Wilson PJ, Jarvis JC, Davidson JS, Hunt JA, Ranganath LR, & Gallagher JA (2011). The role of calcified cartilage and subchondral bone in the initiation and progression of ochronotic arthropathy in alkaptonuria. Arthritis and rheumatism, 63 (12), 3887-96 PMID: 22127706
  • Taylor AM, Boyde A, Davidson JS, Jarvis JC, Ranganath LR, & Gallagher JA (2012). Identification of trabecular excrescences, novel microanatomical structures, present in bone in osteoarthropathies. European cells & materials, 23 PMID: 22522284
  • Treharne KJ, Cassidy D, Goddard C, Colledge WH, Cassidy A, & Mehta A (2009). Epithelial IgG and its relationship to the loss of F508 in the common mutant form of the cystic fibrosis transmembrane conductance regulator. FEBS letters, 583 (15), 2493-9 PMID: 19596328

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

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2014 Crick Symposium on Rare Diseases

The Francis Crick Institute is a new multi-disciplinary medical research institute, and is due to open in 2015. It is a consortium of six UK organisations – the Medical Research Council, Cancer Research UK, the Wellcome Trust, University College London (UCL), Imperial College London, and King’s College London. The consortium members have committed to invest £650 million to establish the institute, which is expected to become a hub of medical research expertise and innovation. Rare diseases are high on the research agenda at the Crick Institute, and they recently hosted a symposium on rare diseases in London, with roughly 450 researchers in attendance.

Genetic research was a popular topic at the meeting, which is not surprising as 80% of rare diseases are thought to have a genetic cause. Currently, whole exome sequencing (WES) is performed more commonly than whole genome sequencing (WGS), as it is faster, cheaper and the results are more straight-forward to interpret. However, Professor Veronica van Heyningen, University of Edinburgh, presented data showing that non-coding mutations in the downstream regulatory region of Pax6 ablate its expression in the eye and cause the developmental eye disorder aniridia (Bhatia et al., 2013). As the cost of sequencing falls and analysis pipelines are improved, research projects will increasingly perform WGS and will likely find many more examples of pathogenic mutations affecting how genes are regulated.

It is estimated that 75% of rare diseases affect children, more than a third of whom will not live to see their 5th birthday. The Dechiphering Developmental Disorders Project, which aims to determine the genetic basis of childhood developmental disorders, was introduced by Dr Matt Hurles, Wellcome Trust Sanger Institute. As of February 2014, 8,000 families have been enrolled in the study which performs WES, array Comparative Genomic Hybridisation, and SNP genotyping on trios (the affected child and both parents) to find de novo coding mutations, copy number variants and uniparental disomies in affected children. Thus far, the project has reported ~1200 causative genes corresponding to 27% of the trios analysed and all results have been deposited in the DECIPHER database, which is a freely available international resource for researchers and clinicians.

New therapies were also discussed by several speakers. Firstly, Professor Tim Aitman, Imperial College London, presented examples of personalised medicines, where treatment is chosen depending on the specific genetic lesions that have caused the disease. This will be discussed in more depth in an upcoming blog post. Professor Fran Platt, University of Oxford, spoke about her work in successfully repurposing the drug Miglustat, which was developed as an HIV treatment, for the lysosomal storage disorders Type I Gaucher’s Disease and Neimann Pick Type C. (Bennet and Mohan, 2013, Lyseng-Williamson, 2014)

Duchenne Muscular Dystrophy (DMD) is caused by mutations that disrupt the reading frame of the Dystrophin gene, causing the RNA transcript to be degraded. Professor Francesco Mutoni, University College London, presented his work on RNA therapy – where anti-sense RNA is injected directly into muscle and causes target exons to be skipped and excluded from the final mRNA transcript. Exon skipping restores the reading frame and allows a truncated form of the protein to be synthesised (Cirak et al., 2013, Kinali et al., 2009). While not a complete cure, RNA therapy halts the progression of DMD, and patients who have received RNA therapy have remained stable for two and half years so far.

The Crick Symposium was an interesting and varied meeting, and showed there is significant interest in rare disease research. Indeed, rare disease research is increasingly viable due to better technology, political pressure and increased patient interest. The Crick Institute aims to become a leader in rare disease research, and is well-placed to do so: there are estimated to be around 500,000 people in London with a rare disease, and 40 out of 70 commissioned rare disease services are in London. Furthermore, at UCL there are already 250 research groups that work on rare diseases, covering roughly 400 diseases, meaning there is already an active research programme in place.

 

  • Bennett LL, & Mohan D (2013). Gaucher disease and its treatment options. The Annals of pharmacotherapy, 47 (9), 1182-93 PMID: 24259734
  • Bhatia S, Bengani H, Fish M, Brown A, Divizia MT, de Marco R, Damante G, Grainger R, van Heyningen V, & Kleinjan DA (2013). Disruption of autoregulatory feedback by a mutation in a remote, ultraconserved PAX6 enhancer causes aniridia. American journal of human genetics, 93 (6), 1126-34 PMID: 24290376
  • Cirak S, Feng L, Anthony K, Arechavala-Gomeza V, Torelli S, Sewry C, Morgan JE, & Muntoni F (2012). Restoration of the dystrophin-associated glycoprotein complex after exon skipping therapy in Duchenne muscular dystrophy. Molecular therapy : the journal of the American Society of Gene Therapy, 20 (2), 462-7 PMID: 22086232
  • Kinali M, Arechavala-Gomeza V, Feng L, Cirak S, Hunt D, Adkin C, Guglieri M, Ashton E, Abbs S, Nihoyannopoulos P, Garralda ME, Rutherford M, McCulley C, Popplewell L, Graham IR, Dickson G, Wood MJ, Wells DJ, Wilton SD, Kole R, Straub V, Bushby K, Sewry C, Morgan JE, & Muntoni F (2009). Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. Lancet neurology, 8 (10), 918-28 PMID: 19713152
  • Lyseng-Williamson KA (2014). Miglustat: a review of its use in Niemann-Pick disease type C. Drugs, 74 (1), 61-74 PMID: 24338084

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

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Cowden Syndrome shares clinical, genetic and biological features with several kidney cancer susceptibility syndromes

Cowden Syndrome is one of several PTEN Hamartoma Tumor Syndromes caused by heterozygous germline mutations in the PTEN gene. Symptoms include learning disability, macrocephaly, skin papules on the face and mucous membranes, intestinal and colonic polyps, uterine fibroids, lipomas, and increased susceptibility to thyroid, breast and endometrial cancers. Two studies, published in 2012 and 2013 suggest that renal cell carcinomas (RCC) may also be a low risk symptom of Cowden Syndrome, and as such, PTEN mutations might be an underappreciated cause of hereditary kidney cancers.

Mester et al. (2012) analysed a cohort of 219 patients with germline PTEN mutations, 9 of whom (4.1%) had a medical history of RCC, and Shuch et al. (2013) investigated a cohort of 24 Cowden Syndrome patients – with confirmed PTEN mutations – 4 of whom (16.7%) had a medical history of RCC. Overall, the prevalence of RCC in patients carrying a PTEN mutation was 5.3% (13/243), and all patients who developed RCC had symptoms consistent with Cowden Syndrome. The increased prevalence of RCC found in the Shuch et al. cohort is likely to be because this cohort was a carefully selected group of patients with particularly prominent symptoms of Cowden Syndrome, whereas the Mester cohort was selected solely on the basis of their PTEN mutation status.

Of the 13 Cowden Syndrome patients with RCC described in these two studies, six had type I papillary RCCs; two had type IIB papillary RCCs; three had chromophobe RCC, two of whom presented with bilateral tumours; one had a clear cell RCC; and tumour histology was not available for one patient. Immunohistochemical staining (Mester et al., 2012) and loss of heterozygosity (LOH) analysis (Shuch et al., 2013) showed that PTEN expression was lost in all but two of the tumour samples analysed. Interestingly, the clear cell RCC tumour showed both LOH of PTEN and had also acquired a somatic truncating mutation in one VHL allele.

Homozygous deletion of both PTEN and VHL has been previously shown to cause liver hemangioblastomas and kidney cysts in mice (Chen et al., 2010; Frew et al., 2008), and compound heterozygosity of PTEN and FLCN has been reported to cause oncocytic tumour growth specifically in the context of Cowden and BHD Syndromes (Pradella et al., 2013). Furthermore, mutations in SDHB and SDHD, which catalyse the step preceding that catalysed by FH in the citric acid cycle, can cause both Familial Paraganglioma Syndrome – another heritable kidney cancer syndrome – and a Cowden-like Syndrome (Ni et al., 2008). Taken together, there is evidence that PTEN interacts genetically with a number of known kidney cancer genes to cause disease.

Loss of PTEN increases PI3K signalling, leading to mTORC1 hyperactivity via dysregulation of the AKT-TSC1/2 signalling axis (Salmena et al., 2008). Dysregulation of mTOR signalling and of HIF1a translation are common features of hereditary kidney cancer syndromes, and as such many known kidney cancer proteins, such as TSC1/2, FLCN, FH, VHL, SDHB, SDHD and TFE3, converge on this pathway (Shuch et al., 2013).

Clinically, Cowden Syndrome has some symptoms that overlap with other kidney cancer susceptibility syndromes in addition to RCC: learning disability, lipomas, fibromas and other types of hamartomas, as in TSC; uterine fibroids, as in HLRCC; colon polyps which are an unconfirmed symptom of BHD; and skin papules as is seen in all three syndromes.

From the above evidence, it seems that there is significant overlap in the clinical symptoms, genetics and molecular biology of Cowden Syndrome with many of the kidney cancer syndromes, including BHD, TSC, HLRCC and VHL. Thus, clinicians should be aware of Cowden Syndrome as a differential diagnosis in patients with kidney cancer, especially if the patient has additional syndromic symptoms.

 

  • Chen S, Sanford CA, Sun J, Choi V, Van Dyke T, Samulski RJ, & Rathmell WK (2010). VHL and PTEN loss coordinate to promote mouse liver vascular lesions. Angiogenesis, 13 (1), 59-69 PMID: 20221685
  • Frew IJ, Thoma CR, Georgiev S, Minola A, Hitz M, Montani M, Moch H, & Krek W (2008). pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation. The EMBO journal, 27 (12), 1747-57 PMID: 18497742
  • Mester JL, Zhou M, Prescott N, & Eng C (2012). Papillary renal cell carcinoma is associated with PTEN hamartoma tumor syndrome. Urology, 79 (5), 11870-7 PMID: 22381246
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www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

pf button Cowden Syndrome shares clinical, genetic and biological features with several kidney cancer susceptibility syndromes

Rare Disease Day 2014: Join Together for Better Care

Today is the seventh international Rare Disease Day. Co-ordinated by EURORDIS and NORD and celebrated on the last day of February, Rare Disease Day was founded to raise awareness about rare diseases. It has grown in popularity each year, with 72 countries having participated in 2013 and the theme for 2014 is “Join Together for Better Care.”

In Europe, a rare disease is defined as one that affects fewer than 1 in 2000 people. However, there are estimated to be between 6000 and 8000 rare diseases, many of which are chronic and debilitating. It is thought that between 6 – 8% of the European population (or roughly 1 in 14 people) has a rare disease, meaning that rare diseases affect a huge number of people. Approximately 80% are genetic, and half affect children, a third of whom are predicted to not live to see their 5th birthday.

Despite having different conditions, rare disease patients often face a very similar set of challenges. A lack of scientific and medical knowledge means many patients have difficulty getting a diagnosis or finding doctors with relevant expertise and often there is no effective treatment or cure. Many rare diseases are multi-systemic, and fragmented care pathways means patients have to visit multiple specialists – sometimes at different hospitals – about the different aspects of their condition, which is time consuming. Additionally, a lack of communication between specialists can sometimes mean that doctors are working at cross-purposes, and causing harm to the patient. Access to medical and social care can be uneven and subject to local resources rather than patient need and patients often feel isolated due to a lack of support and information.

Although these challenges are significant, they are not insurmountable and a number of initiatives are aiming to help rare disease patients overcome these hurdles. Research consortia and companies like IRDiRC and Genomics England will improve diagnosis rates: IRDiRC is aiming to establish the means to diagnose most rare diseases by 2020, and Genomics England will sequence the genomes of tens of thousands of rare disease patients to determine the genetic cause of their disease. These research insights will inevitably aid researchers in developing rare disease therapies, and IRDiRC hopes to have developed 200 therapies by 2020 – they have already developed 105 therapies since their establishment in 2010, meaning they are well on their way to achieving this goal.

In Europe, all EU member states submitted rare disease strategies in 2013, describing how they will provide better healthcare for patients with rare diseases, and the UK Strategy for Rare Diseases was launched in November. The UK Strategy for Rare Diseases concentrates on five main areas: identifying and preventing rare diseases; diagnosis and early intervention; coordination of care; the role of research; and empowering patients, encouraging them to have a greater role in decision making about their own care (Salzberg Global Seminar, 2011). Additionally, there are a number of projects that have established multi-disciplinary centres and care co-ordinators for those with rare diseases, such as new NHS multi-disciplinary clinics for patients with Alström Syndrome.

A number of events are planned for Rare Disease Day in the UK, including parliamentary receptions, and a showcase of rare disease research for school children at Royal Holloway, part of the University of London. For more information on events near you, and how you can support Rare Disease Day, please visit the Rare Disease Day 2014 website.

 

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

pf button Rare Disease Day 2014: Join Together for Better Care