Danielle Stevenson

198 posts · 75,643 views

BHD Research Blog
198 posts

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  • July 24, 2015
  • 05:07 AM
  • 103 views

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 candid........ 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
  • 27 views

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 gene........ Read more »

  • July 10, 2015
  • 04:31 AM
  • 83 views

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%........ 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
  • 185 views

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 form........ 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
  • 127 views

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
  • 79 views

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 survi........ Read more »

  • May 22, 2015
  • 04:07 AM
  • 192 views

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
  • 152 views

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 ........ 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
  • 178 views

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 im........ Read more »

  • April 24, 2015
  • 09:00 AM
  • 100 views

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
  • 300 views

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 nat........ 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
  • 327 views

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 ........ 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  

  • April 10, 2015
  • 09:00 AM
  • 202 views

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 ........ 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  

  • March 27, 2015
  • 09:00 AM
  • 136 views

Fnip1 and Fnip2 play critical roles in kidney tumour suppression in cooperation with Flcn in mice

by Danielle Stevenson in BHD Research Blog

Folliculin (FLCN), through its association with renal tumours in BHD and knockout mouse models, is now recognised as a tumour suppressor. The loss of Flcn in kidney cells is linked to pro-tumourigenic changes in AMPK and mTOR activity, increased expression of PPARGC1A (PGC1α) and increased mitochondrial biogenesis (Baba et al., 2008, Hasumi et al., 2012). Two folliculin interacting proteins, FNIP1 and FNIP2, are known to facilitate FLCN function. A report from Hasumi et al., 2015 aimed to clari........ Read more »

Hasumi H, Baba M, Hasumi Y, Lang M, Huang Y, Oh HF, Matsuo M, Merino MJ, Yao M, Ito Y.... (2015) Folliculin-interacting proteins Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn. Proceedings of the National Academy of Sciences of the United States of America. PMID: 25775561  

  • March 13, 2015
  • 09:00 AM
  • 111 views

Differential effects of HIF-α isoforms on apoptosis in renal carcinoma cell lines

by Danielle Stevenson in BHD Research Blog

Under hypoxic conditions the activation of HIF transcription factors enables cells to alter their metabolism and avoid stress-induced apoptosis. Aberrant HIF activity in the inherited renal cancers BHD, VHL, HLRCC and TSC, is linked to the expression of growth and pro-angiogenic factors that are important in tumour growth. A new report from Doonachar et al., (2015) focuses on the differential effects of the HIF-1α and HIF-2α isoforms on stress-induced apoptosis in two VHL-deficient r........ Read more »

Doonachar A, Gallo MD, Doukas D, Pasricha R, Lantsberg I, & Schoenfeld AR. (2015) Differential effects of HIF-α isoforms on apoptosis in renal carcinoma cell lines. Cancer cell international, 23. PMID: 25729330  

  • March 12, 2015
  • 11:31 AM
  • 205 views

Distinctive expression patterns of FLCN and GPNMB in BHD renal tumours

by Danielle Stevenson in BHD Research Blog

As discussed on this blog previously, developing histological screening techniques for renal cell carcinomas (RCCs) associated with BHD is important for early diagnosis. Individuals with folliculin (FLCN) mutations are more likely to develop multiple bilateral renal tumours (Zbar et al., 2002, Pavlovich et al., 2002). A misdiagnosis of sporadic RCC may compromise future treatment and wellbeing of the patient and other affected family members. Currently there are no known histological markers to ........ Read more »

  • February 13, 2015
  • 09:00 AM
  • 107 views

Characterisation of renal tumours in patients with Birt-Hogg-Dubé Syndrome

by Danielle Stevenson in BHD Research Blog

Due to mutations in their folliculin (FLCN) gene Birt-Hogg-Dubé (BHD) syndrome patients have a greater risk of developing renal cell carcinomas (RCC) than others (Zbar et al., 2002, Houweling et al., 2011). Unlike sporadic cases of RCC, where the majority are classified as clear cell RCC (ccRCC), studies of FLCN-related tumours have found that the majority are either chromophobe RCCs (34%) or hybrid oncocytoma/chromophobe tumours (HOCTs, 50%) with fewer cases of ccRCC (9%) and only rare o........ Read more »

Iribe Y, Kuroda N, Nagashima Y, Yao M, Tanaka R, Gotoda H, Kawakami F, Imamura Y, Nakamura Y, Ando M.... (2015) Immunohistochemical characterization of renal tumors in patients with Birt-Hogg-Dubé Syndrome. Pathology international. PMID: 25597876  

  • January 30, 2015
  • 09:00 AM
  • 92 views

The development of targeted therapy for renal cell carcinoma

by Danielle Stevenson in BHD Research Blog

Over 85% of kidney and renal pelvis cancers are renal cell carcinomas (RCC); a disease with multiple subtypes including clear cell, papillary, chromophobe and oncocytomic. The variable nature of RCC makes one blanket treatment impossible, and therefore targeted therapies may be more effective at enhancing survival. A recent review from Randall et al., (2014) summarises the current knowledge on RCC genetic aberrations and their effects, as well as discussing current and future treatment options.... Read more »

  • January 23, 2015
  • 09:00 AM
  • 195 views

Fnip1 regulates skeletal muscle fibre type specification, fatigue resistance, and susceptibility to muscular dystrophy

by Danielle Stevenson in BHD Research Blog

Summary of recent paper into the role of Fnip1 in skeletal muscle development.... Read more »

Reyes NL, Banks GB, Tsang M, Margineantu D, Gu H, Djukovic D, Chan J, Torres M, Liggitt HD, Hirenallur-S DK.... (2015) Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy. Proceedings of the National Academy of Sciences of the United States of America, 112(2), 424-9. PMID: 25548157  

  • January 23, 2015
  • 03:00 AM
  • 201 views

Fnip1 regulates skeletal muscle fibre type specification, fatigue resistance, and susceptibility to muscular dystrophy

by Danielle Stevenson in BHD Research Blog

Folliculin (FLCN) and the associated folliculin-interacting proteins FNIP1 and FNIP2 have been shown to play a role in cell metabolism through regulation of the AMPK-mTOR pathways. Previously Hasumi et al. (2012) reported that selective deletion of Flcn in mouse skeletal … Continue reading →... Read more »

Reyes NL, Banks GB, Tsang M, Margineantu D, Gu H, Djukovic D, Chan J, Torres M, Liggitt HD, Hirenallur-S DK.... (2015) Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy. Proceedings of the National Academy of Sciences of the United States of America, 112(2), 424-9. PMID: 25548157  

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