Danielle Stevenson

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BHD Research Blog
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  • September 18, 2015
  • 04:19 AM

Use of Cavitation Ultrasonic Surgical Aspirators for partial nephrectomies

by Danielle Stevenson in BHD Research Blog

Partial nephrectomies are technically challenging surgeries but preserve healthy renal tissue and therefore function. To minimise bleeding the major blood vessels are usually clamped and tumour extraction completed under ischemic conditions – the renal tissue is deprived of oxygen and nutrients due to restricted blood flow. Although ischemic conditions for less than 25 minutes have minimal reported impact on renal function (Volpe et al., 2015), more complex tumours result in prolonged ischemia making the preservation of healthy tissue more difficult. In recent years several zero-ischemic techniques, including minimally invasive and robotic approaches (Gill et al., 2011, Simone et al., 2013), have been developed that do not require renal artery clamping.... Read more »

  • September 11, 2015
  • 09:00 AM

Upcoming BHD and Upstate Kidney Cancer Symposium

by Danielle Stevenson in BHD Research Blog

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

  • September 4, 2015
  • 06:08 AM

Everolimus for the treatment of lymphangioleiomyomatosis

by Danielle Stevenson in BHD Research Blog

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

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

  • August 28, 2015
  • 09:00 AM

Immunotherapy AGS-003 trial in localised renal cell carcinoma

by Danielle Stevenson in BHD Research Blog

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

  • August 21, 2015
  • 09:00 AM

TDP-43 differentially splices FNIP1

by Danielle Stevenson in BHD Research Blog

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

  • August 14, 2015
  • 09:00 AM

Sharing genomic data to advance research

by Danielle Stevenson in BHD Research Blog

It is expected that genetic sequencing will advance both specialised and general healthcare leading to more personalised care based on an individual’s genome. It can be used to identify disease-specific mutations and those associated with more complex conditions. However, as discussed previously on this blog, understanding the effect of a single mutation can be difficult without comparison between healthy and disease patient samples. Sharing patient data accumulated by private and academic labs, voluntary databases, healthcare providers and large scale sequencing efforts such as the 100,000 genomes project, can provide researchers with the larger datasets required for accuracy.... Read more »

  • August 7, 2015
  • 09:00 AM

High-throughput screening to identify synthetic lethal compounds in RCC

by Danielle Stevenson in BHD Research Blog

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

  • July 31, 2015
  • 04:13 AM

Everolimus: a new treatment for BHD renal cancer?

by Danielle Stevenson in BHD Research Blog

Last week the US National Cancer Institute announced a phase II clinical trial to test everolimus, a derivative of rapamycin, in BHD patients with renal cell carcinoma (RCC). The trial is also open to sporadic chromophobe RCC (chRCC) patients. Approximately 85% of BHD-RCC is either chRCC or a chromophobe-oncocytoma hybrid (Pavlovich et al., 2002), but there are no effective treatments available for this RCC subtype. Instead BHD patients undergo partial nephrectomies to excise tumours – while not often impacting greatly on renal function, repetitive surgeries can increase morbidity risks. It is hoped that cancer drugs, such as everolimus, can offer a valid alternative treatment.... Read more »

  • July 24, 2015
  • 05:07 AM

Analysing mutational heterogeneity to identify true cancer-associated genes

by Danielle Stevenson in BHD Research Blog

A recent blog post discussed the need to assess the pathogenicity of genetic variants to determine which mutations are truly causative and which are only background. This is highly important in the search for new cancer drugs as rapidly dividing tissues are more prone to accruing mutations. Large cancer genomic studies are identifying increasing numbers of apparently “significantly-mutated genes” across all major cancer types. However, these genes often include highly unlikely candidates. Analysis of 178 squamous lung cell carcinomas identified 450 significantly-mutated genes; almost a quarter of which were olfactory receptors (TCGA Research Network, 2012). It is necessary to be able to eliminate these false-positives and retain focus on true cancer-genes.
... Read more »

Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA.... (2013) Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature, 499(7457), 214-8. PMID: 23770567  

  • July 17, 2015
  • 09:00 AM

Distinct roles for VHL and hypoxia in RCC gene expression and metabolism

by Danielle Stevenson in BHD Research Blog

As discussed in last week’s blog renal cell carcinoma (RCC) cells show altered metabolism favouring lactate fermentation as the major energy source. Such metabolic changes can be a response to hypoxia or mutations in genes, such as VHL, that disrupt HIFα-proteasomal degradation. HIF signalling, directly and indirectly, regulates over 2% of human genes including those involved in angiogenesis, survival, proliferation and metabolism (Manalo et al., 2005). Hypoxia and VHL-loss are generally thought to result in the same changes in gene and protein expression, however, Leisz et al., (2015) have found differential effects in RCC cellular models.... Read more »

  • July 10, 2015
  • 04:31 AM

Grade-dependent metabolic reprogramming in RCC

by Danielle Stevenson in BHD Research Blog

It is well established that altered metabolism in cancer cells supports survival and growth. Understanding these biological changes could lead to treatments able to specifically target tumourigenic cells. However, despite the known variability in tumour biology, the majority of research is based on the same available cell lines. In renal cell carcinoma (RCC) research these lines frequently carry a VHL mutation: VHL gene alterations are associated with hereditary RCC in VHL syndrome and up to 91% of sporadic clear cell RCCs (Nickerson et al., 2008). The loss of pVHL results in aberrant HIF signalling and changes in metabolism (Keefe et al., 2013).... Read more »

Wettersten HI, Hakimi AA, Morin D, Bianchi C, Johnstone ME, Donohoe DR, Trott JF, Aboud OA, Stirdivant S, Neri B.... (2015) Grade-Dependent Metabolic Reprogramming in Kidney Cancer Revealed by Combined Proteomics and Metabolomics Analysis. Cancer research, 75(12), 2541-52. PMID: 25952651  

  • July 3, 2015
  • 06:06 AM

A new tissue-specific FLCN-deficient mouse model of renal tumourigenesis

by Danielle Stevenson in BHD Research Blog

Animal models can be useful for understanding disease pathology and as preclinical models for drug testing. As BHD patients develop renal cell carcinomas (RCCs) of varied histologies, associated with a loss of FLCN, BHD animal models could be used to study of a wide range of renal cancer subtypes. Current BHD mouse models include kidney-specific Flcn-knockouts (Chen et al., 2008, Baba et al., 2008) and ubiquitous knockouts (Hasumi et al., 2009, Hartman et al., 2009, Hudon et al., 2010). The former develop polycystic kidneys and die within three weeks, the latter can only be studied as heterozygotes with tumourigenesis dependent on a “second hit” resulting in variable penetrance and making them less suitable for drug studies.... Read more »

Chen J, Huang D, Rubera I, Futami K, Wang P, Zickert P, Khoo SK, Dykema K, Zhao P, Petillo D.... (2015) Disruption of tubular Flcn expression as a mouse model for renal tumor induction. Kidney international. PMID: 26083655  

  • June 12, 2015
  • 04:07 AM

A lactate-induced response to hypoxia

by Danielle Stevenson in BHD Research Blog

Hypoxia regulation ensures cell survival and growth in low oxygen environments. HIF signalling is a well-established element of this regulation but is also associated with tumourigenesis in BHD, VHL, HLRCC, TSC, and sporadic cancers. New research from Lee et al., (2015) has identified a second, HIF-independent, hypoxia response which can modify cell survival and growth signalling pathways – the lactate-induced activation of NDRG3-mediated signalling.... Read more »

Lee DC, Sohn HA, Park ZY, Oh S, Kang YK, Lee KM, Kang M, Jang YJ, Yang SJ, Hong YK.... (2015) A lactate-induced response to hypoxia. Cell, 161(3), 595-609. PMID: 25892225  

  • May 29, 2015
  • 09:00 AM

The potential use of BH3-mimetics to overcome apoptosis-resistance in renal cell carcinoma

by Danielle Stevenson in BHD Research Blog

Renal cell carcinoma (RCC), as well as other solid tumours, can prove resistant to standard cancer treatments such as chemotherapy. One mechanism likely to play a role in this resistance is activation of HIF signalling either as a result of hypoxia within the tumour or as the result of mutations as in BHD, VHL and TSC. Increased HIF activity, as well as altered PI3K/AKT/mTOR, MEK/ERK and TGFβ signalling, can shift the balance of anti- and pro-apoptotic factors enabling tumour cells to survive in unfavourable conditions.... Read more »

  • May 22, 2015
  • 04:07 AM

Clinical trials for rare diseases – finding and keeping patients

by Danielle Stevenson in BHD Research Blog

International Clinical Trial day (May 20th) celebrates the medical advances as a result of clinical trials. Clinical trials are essential to ensure drug safety and efficacy, and the recent increase in the development of orphan drugs has led to an increase in rare disease clinical trials. The nature of rare diseases creates specific challenges for clinical trial design and patient recruitment.... Read more »

  • May 15, 2015
  • 04:12 AM

A role for Matrix Metalloproteinases in BHD?

by Danielle Stevenson in BHD Research Blog

The BHD protein folliculin (FLCN) plays a role in numerous signalling pathways and cellular processes. Although mutations in FLCN are only firmly linked to the development of fibrofolliculomas, pulmonary cysts and renal tumours it is possible that disruption of these pathways also plays a role in other phenotypes. Recently Kapoor et al., (2015) reported three cases studies of women with BHD who presented with intracranial vascular pathologies. There are few other reports of vascular pathologies in BHD and further studies would be required to determine any causative link. Kapoor et al. proposed two hypotheses to link BHD to aneurysms and vascular malformations: aberrant HIF-1α signalling and increased matrix metalloproteinase 9 (MMP-9) activity.... Read more »

Kapoor R, Evins AI, Steitieh D, Bernardo A, & Stieg PE. (2015) Birt-Hogg-Dubé syndrome and intracranial vascular pathologies. Familial cancer. PMID: 25952757  

  • May 8, 2015
  • 04:13 AM

Advances in immunotherapy for renal cell carcinoma

by Danielle Stevenson in BHD Research Blog

In recent years there has been renewed interest in immunotherapies to treat of metastatic renal cell carcinoma (mRCC). Immunotherapies increase the body’s natural finely regulated multiple-step anti-tumour immune response (Figure 1). The balance of stimulatory and inhibitory signals (reviewed in Chen & Mellman, 2013) are important in maintaining self-tolerance and modulating normal immune responses to minimising health tissue damage. However, tumours can develop mechanisms to evade this immune response.... Read more »

  • April 24, 2015
  • 09:00 AM

FindZebra: a specialised search engine for rare diseases

by Danielle Stevenson in BHD Research Blog

Every doctor is taught to think of the common causes of a problem before contemplating the rare ones. This works for the majority of patients but occasionally the cause is something unusual – a “zebra” – and isn’t so easy to find. For rare disease patients a specific diagnosis can be elusive with 46% receiving at least one incorrect diagnosis and 20% waiting over five years for a final diagnosis (Rare Disease UK, 2010).... Read more »

Dragusin R, Petcu P, Lioma C, Larsen B, Jørgensen HL, Cox IJ, Hansen LK, Ingwersen P, & Winther O. (2013) FindZebra: a search engine for rare diseases. International journal of medical informatics, 82(6), 528-38. PMID: 23462700  

  • April 17, 2015
  • 04:38 AM

Rhabdomyomas: an additional BHD hamartoma phenotype?

by Danielle Stevenson in BHD Research Blog

Hamartomas are benign, focal malformations formed by an excess of normal tissue growing in a disorganised fashion. Several hamartoma syndromes have been linked to aberrant mTOR signalling including BHD and Tuberous Sclerosis Complex (TSC). In addition to the predisposition of BHD patients to develop hair follicle hamartomas or fibrofolliculomas (Birt et al., 1977), Fuyura et al., (2012) propose that the pulmonary cysts in BHD patients are hamartoma-like cystic alveolar formations. The benign nature of these BHD growth phenotypes, in comparison to the potentially malignant growth of BHD renal cell carcinomas, shows that folliculin (FLCN) haploinsufficiency gives a less severe pathology than FLCN loss-of-function.

A recently published study from Bondavalli et al., (2015) was the first report of a cardiac rhabdomyoma (hamartoma) in an infant carrying a FLCN mutation. Cardiac rhabdoyomas are the most common cardiac tumour in children and can be sporadic or syndromic. Syndromic cardiac rhabdomyomas are associated with TSC and mutations in the TSC1 and TSC2 genes, however no such mutations were found in the infant.... Read more »

Bondavalli D, White SM, Steer A, Pflaumer A, & Winship I. (2015) Is cardiac rhabdomyoma a feature of Birt Hogg Dubé syndrome?. American journal of medical genetics. Part A, 167(4), 802-4. PMID: 25655561  

  • April 10, 2015
  • 09:00 AM

Intragenic deletions in folliculin identified and mapped

by Danielle Stevenson in BHD Research Blog

The phenotypes associated with BHD – fibrofolliculomas, pulmonary cysts with an increased risk of pneumothorax, and an increased risk of renal cell carcinoma (RCC) – show variable penetrance between and within families, making diagnosis difficult when only one symptom is present. Studies have found that up to 10% of patient cohorts diagnosed with Primary Spontaneous Pneumothorax (PSP) have folliculin (FLCN) mutations (Ren et al., 2008, Johannesma et al., 2015).

Patients suspected of having BHD undergo genetic testing via DNA sequencing to detect FLCN mutations. However, for a minority patients with clinical BHD no mutation can be detected using these techniques. Large intragenic deletions and duplications have been identified in such patients (Kunogi et al., 2010, Sempau et al., 2010, Benhammou et al., 2011). New work from Ding et al., (2015) has identified and mapped three large intragenic deletions in the FLCN genes of 40 patients from nine Chinese families with a family history of PSP and lung cysts.
Ding et al., (2015) analysed 12 families in total including five families identified in Ren et al., (2008) that were found not to have small mutations detectable by DNA sequencing. The families showed reduced fibrofolliculoma penetrance and no RCC. The families were identified through a proband admitted after a spontaneous pneumothorax, so this selection bias might make the reduction in fibrofolliculomas and RCC less significant. Larger comparative studies are required to determine if there are significant difference in phenotype penetrance in different ethnic groups.‎

Ding et al., used Multiplex Ligation-Dependent Probe Amplification (MLPA) and breakpoint analysis to identify a large deletion across exons 9-14 (c.872-492_1740 1763del) in five families, a deletion across exon 14 (c.1539-536_1740 1701del) in two families and a large deletion across exons 1-3 (c.-504-1303_-25 845del) in two families. The FLCN start codon is in exon 4 therefore deletion of exons 1-3 would disrupt the promotor reducing expression (Benhammou et al., 2011). The other deletions would prematurely truncate FLCN and as several identified functions rely on the C-terminal (Baba et al., 2006) these mutations would be pathogenic.

A 5.5Mb disease haplotype was identified around the exon 9-14 deletion suggesting a founder mutation. In addition all five families shared a point mutation in exon 5. This deletion was estimated to have occurred approximately 16 generations ago. Haplotypes around the exon 14 and exon 1-3 deletions were also found, however estimating the age was not possible from two families.

To date one large intragenic duplication and 11 large intragenic deletions (Figure 1) have been identified in 20 BHD families and 2 sporadic patients. Two of the deletions identified by Ding et al., have previously been reported (Kunogi et al., 2010) but not mapped in detail. The three deletions mapped in this work and several of the other deletions have AluI repeat sequences (black arrows in Figure 1) on either side. Interestingly the FLCN gene has a high density of AluI repeats compared to the genome in general and this increases the risk of homologous recombination resulting in deletions and duplications.

This work supports the conclusion that a percentage of PSP patients are actually undiagnosed BHD patients, and that the 10% previously suggested could be an underestimation if only DNA sequencing is used to detect FLCN mutations. MLPA analysis would therefore be an important and useful additional DNA testing tool for detecting mutations in suspected BHD patients.... Read more »

Ding Y, Zhu C, Zou W, Ma D, Min H, Chen B, Ye M, Pan Y, Cao L, Wan Y.... (2015) FLCN intragenic deletions in Chinese familial primary spontaneous pneumothorax. American journal of medical genetics. Part A. PMID: 25807935  

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