Searching for ‘Birt Hogg Dubé’ results in 12 different models of molecular pathogenesis underlying renal cell carcinoma (RCC) in several species. Three excellent schematics are provided illustrating which signalling pathways are deregulated in several types of RCC in homo sapiens.

The beginning of a BHD specific pathway is also provided, but has yet to be completed. I’ll provide a direct link to the page in question (here) so you can see for yourselves. I’ve found it’s useful when thinking about FLCNs role in renal tumourigenesis within the context of ‘the bigger picture’. The models provided are all RCC centric for the time being but that obviously reflects the quality of work done in the area. I hope that in the coming years we can flesh out the ‘BHD’ section a lot more!

I’d like to take this opportunity to encourage as many researchers as possible to attend, as the day will be an interesting mix of talks and poster presentations addressing both the clinical and basic scientific aspects of BHD Syndrome (and I use the term ‘basic’ loosely).

Having previously worked in the lab for a number of years, I often attended a number of various conferences but almost always left underwhelmed since quite often, only one or two talks were applicable to my specific area of interest and even then, the further applications or insights into my own research were tenuous at best.

However, if your work is in anyway related to BHD Syndrome then the Second BHD Symposium 2010 really should be a date in your diary. Very rarely will you find a whole day dedicated to your area, and as a result of the BHD field being quite small you’ll get to hear from highly respected researchers from around the world. Since the last Symposium in 2008, so much more is understood about the molecular biology and biochemistry underlying BHD Syndrome and the number of groups involved in BHD research has increased. Further characterisation of Folliculin has been carried out as well as the collection of clinical data from larger BHD cohorts across the globe – can you afford to miss out?

Up to date information regarding the Second BHD Symposium, including how to register and accommodation details can be found here. Travel grants are available from the Myrovlytis Trust.

This event is much needed and does a lot for the rare disease ’cause’ and I’d just like to take this opportunity to remind everyone that for some people, everyday is a rare disease day.

Undoubtedly, no comfort is gained in being diagnosed with the commonest of cancers, but prompt clinical management and treatment can not only be re-assuring but a real lifeline too. Often however, the positive diagnosis of a rare syndrome is often itself a struggle, let alone prompt and comprehensive treatment.

The organisers of Rare Disease Day correctly point out that there is ‘a lack of specific health policies, a scarcity of expertise and little research’ in the area of so-called ‘Orphan Diseases’ and that by increasing the awareness of ‘rare disease’ in the public consciousness, this matter can be addressed.

www.BHDsyndrome.org aims to be the primary online resources for individuals interested in, or affected by BHD Syndrome, a rare genetic disease.

For more details on the second BHD Symposium, including how to submit and abstract, register and accommodation listings, see here

The dependence of HLRCC tumours on glycolysis as a means of obligate anaerobic respiration, coupled with their impaired mitochondrial respiration, mark this renal cancer as a unique example of Warburg’s hypothesis. This hypothesis suggests the tumours forgo the Kreb’s cycle as a means of ATP generation, instead, preferentially using glyclolysis (Ganapathy et al, 2009).

These findings suggest that interference of glycolytic flux may represent a targeted approach to therapy for HLRCC. BHD syndrome is phenotypically similar to HLRCC in that it is characterised by the growth of cutaneous and renal lesions (as well as pulmonary cysts) albeit less severely. Both syndromes share an element of HIF dysfunction: biallelic loss of FH results in aberrant signalling mediated through HIF dependent pathways (Sudarshan et al, 2007) and Weppler et al, (2008) presented data at the Inaugural BHD Symposium which showed that BHD patients may have aberrant HIF activity that was thought to contribute to the development of skin and kidney tumours.

A method similar to that used by Yang et al, (2010) could be used on the FLCN null cell line UOK257 (human RCC derived from a BHD patient), or any BHD animal model, to investigate the status of glycolysis and aerobic respiration could prove useful in expanding our understanding of the pathogenic mechanism underlying BHD syndrome.

References:

Ganapathy V,Thangaraju M, Prasad PD. 2009. Nutrient transporters in cancer: Relevance to Warburg hypothesis and beyond. Pharmacology & Therapeutics, 121(1); 29-40

Launonen V, Vierimaa O, Kiuru M, Isola J, Roth S, Pukkala E, Sistonen P, Herva R, Aaltonen LA. 2001. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci USA 98:3387–3392.

Sudarshan S, Linehan WM, Neckers L. 2007. HIF and fumarate hydratase in renal cancer.  Br J Cancer. 96(3): 403–407.

Weppler SA et al, 2008. Folliculin-dependent regulation of HIF2-alpha. Familial Cancer, 7 (Supplement 1)

Yang Y, Valera VA, Padilla-Nash HM, Sourbier C, Vocke CD, Vira MA, Abu-Asab MS, Bratslavsky G, Tsokos M, Merino MJ, Pinto PA, Srinivasan R, Ried T, Neckers L, Linehan WM. 2010. UOK 262 cell line, fumarate hydratase deficient (FH-/FH-) hereditary leiomyomatosis renal cell carcinoma: in vitro and in vivo model of an aberrant energy metabolic pathway in human cancer. Cancer Genet Cytogenet. 196(1):45-55.

Yang Y, Nash HM, Vira MA, Abu-Asab MS, Val D, Worrell R, Tsokos M, Merino MJ, Pavlovich CP, Ried T, Linehan WM, and Vocke CD.2008. The UOK 257 Cell Line – A Novel Model for Studies of the Human Birt-Hogg-Dubé Gene Pathway. Cancer Genet Cytogenet. 180(2): 100–109.

We could speculate that the mechanism underlying renal tumourigenesis is a multi-step process where renal cysts develop initially and the accumulation of genetic instability results in tumourigenesis and the development of malignant renal tumours. However if this process is ‘universal’ how do we explain the absence of pulmonary tumours in BHD syndrome? So, the question of why pulmonary cysts do not develop into pulmonary tumours remains unanswered.

One suggestion would be that the lung cysts rupture once they are a certain size, preventing the transition to tumourigenic growth. Why cyst development is specific to the outer surface of the lungs is also an outstanding issue, since renal tumours are multifocal. One idea is that the mechanism instigating cystic growth through to tumourigenic development is the same in the lung and the kidney, but that pulmonary tumours never develop due to cyst rupture. Alternatively, could each organ have a specific mechanism which would result in the different phenotypes?

How do we shed light on what is happening in the BHD lung? One method could be to examine the underlying mechanism of pulmonary tumourigenesis in incidences known to have a genetic component in order to uncover dysfunctions in non-BHD related cell signalling pathways, or lung specific tumour suppressors or oncogenes, that might be potentially implicated in BHD syndrome.

Tobacco use accounts for up to 90% of lung cancer incidence, however the remaining 10% of cases are thought to have a genetic or familial component (Peto et al, 2006). A major familial lung cancer susceptibility locus was first identified in 2004 (Bailey-Wilson et al,) using genome wide linkage analysis to identify the major susceptibility locus. Fine-mapping of the region, subsequently, by You et al, (2009) determined that the RGS17 gene was over-expressed in familial lung cancer.

RGS17 encodes a member of the regulator of G-protein signalling family. This protein contains a conserved, 120 amino acid motif called the RGS domain and a cysteine-rich region. The protein attenuates the signalling activity of G-proteins by binding to activated, GTP-bound G alpha subunits and acting as a GTPase activating protein, increasing the rate of conversion of the GTP to GDP. As well as being associated with lung cancer, RGS17 has been shown to be over expressed in prostate cancer, associated with its ability to promote cyclic AMP (cAMP)-responsive element binding protein (CREB)-responsive gene expression, increase cAMP levels, and enhance forskolin-mediated cAMP production (James et al, 2009).

Ultimately, studies such as those by You et al, (2009) contribute further to our understanding of lung cancer susceptibility but since research into the pathogenic mechanism of RGS17 is fairly recent, how it contributes to pulmonary tumourigenesis is still unknown. However, by maintaining an awareness of RGS17 research, we might gain insights into potentially insightful elements of pulmonary tumourigenesis which may shed light on the mechanisms underlying the pulmonary phenotype of BHD Syndrome.

References:

Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, Esposito D, Gillette WK, Hopkins 3rd RF, Hartley JL, Furihata M, Oishi S, Zhen W, Burke Jr. TR, Linehan WM, Schmidt LS and Zbar B. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signalling. Proc. Natl. Acad. Sci. USA 2006; 103, pp. 15552–15557.

Bailey-Wilson et al, 2004. A major lung cancer susceptibility locus maps to chromosome 6q23-25. Am J Hum Genet;75(3):460-74.

Hasumi H, Baba M. Hong SB, Hasumi Y, Huang Y, Yao M, Valera VA, Linehan WM. and Schmidt L.S., Identification and characterization of a novel folliculin-interacting protein FNIP2, Gene 2008; 415: 60–67.

James MA, Lu Y, Liu Y, Vikis HGand You M, (2009). RGS17, an Overexpressed Gene in Human Lung and Prostate Cancer, Induces Tumor Cell Proliferation Through the Cyclic AMP-PKA-CREB Pathway. Cancer Research 69, 2108.

Michael A. James, Yan Lu, Yan Liu, Haris G. Vikis and Ming You. 2009. RGS17, an Overexpressed Gene in Human Lung and Prostate Cancer, Induces Tumor Cell Proliferation Through the Cyclic AMP-PKA-CREB Pathway. Cancer Research 69, 2108.

Peto R, Lopez AD, Boreham J et al. (2006). Mortality from smoking in developed countries 1950–2000: Indirect estimates from National Vital Statistics. Oxford University Press. ISBN 0-19-262535-7

Takagi Y, Kobayashi T, Shiono M, Wang L, Piao X, Sun G, Zhang D, Abe M, Hagiwara Y, Takahashi K. and Hino O, Interaction of folliculin (Birt–Hogg–Dubé gene product) with a novel Fnip1-like (FnipL/Fnip2) protein, Oncogene 27 (2008), pp. 5339–5347.

You et al, 2009; Fine Mapping of Chromosome 6q23-25 Region in Familial Lung Cancer Families Reveals RGS17 as a Likely Candidate Gene. Clinical Cancer Research April 2009 15; 2666.

Of the 14 people in my family that have been tested so far, 14 out of 14 have tested positive for BHDS. This seems to defy all odds, especially given that 8 of these people are asymptomatic.

Does any one have any ideas, are we really unlucky or is something else going on?

The abstract submission deadline for the second BHD Symposium is Monday 15th February. Interested researchers wishing to present data at the Symposium are encouraged to submit their abstracts. The word limit has been set at 200 words.

You can find out more information about the second BHD Symposium and submit your abstract here. ]]> http://www.bhdsyndrome.org/forum/bhd-resources/bhd-symposium-abstract-deadline-reminder/feed/ 0 http://www.bhdsyndrome.org/forum/bhd-research-blog/bhd-syndrome-and-cowdens-disease/ http://www.bhdsyndrome.org/forum/bhd-research-blog/bhd-syndrome-and-cowdens-disease/#comments Fri, 29 Jan 2010 15:25:06 +0000 Duncan Azzopardi http://www.bhdsyndrome.org/?p=1823 Cowden’s disease is an autosomal dominant syndrome characterised by the development of multiple mucocutaneous lesions, benign tumours and enhanced cancer predisposition. Phenotypically this sounds very familiar to the triad of symptoms that characterise BHD: fibrofolliculoma development, renal cancer and the development of pulmonary cysts which lead to pneumothorax.

Cowden’s disease is caused by loss of function of the PTEN tumour suppressor gene. This gene encodes a lipid phosphatase, PTEN, which inhibits the PI3K-AKT signaling pathway. Loss of this function is accompanied by constitutive activation of the PI3K-AKT signaling pathway which leads to uncontrolled cellular proliferation.

Hasumi et al, (2009) showed that kidney tumours from a BHD heterozygous mouse model had increased levels of total AKT  as well as increased AKT phosphorylation, indicating that both PTEN and FLCN could be upstream modulators of AKT, which lends itself to the phenotypic similarities resulting from inactivation of these genes.

So what can be learned from this similarity? There is currently no cure for Cowden’s disease, but several clinical trials are investigating the efficacy of mTOR inhibitors (e.g. Sirolimus) in humans, since AKT inhibitors have undesirable side effects. The use of mTOR inhibitors as a potential therapy for BHD syndrome is not novel since FLCN has been implicated in the mTOR signalling pathway for a good few years now, nevertheless it will be interesting to see how these clinical trials pan out since the clinicians researching Cowden’s disease have a bit of a head start over their counterparts in the BHD field.

To cut a long story short, I found your website and went off to see my GP with the information and photographs.  Although she had not heard of BHD she was genuinely interested and referred me to a dermatologist at Warwickshire Nuffield called Bruce Gee who was brilliant, it was such a relief to speak to someone that knew about BHD.  Dr Gee took biopsies and subsequently confirmed that the lesions are fibrofolliculomas.

I am now awaiting genetic testing at Birmingham Womens Hospital.  I have four brothers all of whom have children (I do not have children).  One of my brothers has similar lesions on his face.  There has be no diagnosed history of BHD in our family but there have been cancers in one side of the family.

I will update when I complete my genetic testing.

Ruth