Pneumothorax Clinical Trials and BHD

After adding the paper ‘Skin tumors as marker lesions for tumor syndromes’ by Mentzel et al (Pathologe. 2010 Oct;31(6):489-96) to the BHD Literature Database, I wondered how informative spontaneous pneumothorax incidences would be for BHD Syndrome.

BHD is generally though to be mis- or under-diagnosed because of the variability of its symptoms. However, more often than not, the majority of published case studies of BHD Syndrome come to be diagnosed either because of the occurrence of fibrofolliculomas or renal cancer, but you don’t often see this for the lung aspect of BHD. In a perfect world, I’m sure that well informed clinicians would recommend a FLCN gene test if presented with any combination of these symptoms, but we know that this is notalways the case in practice.

After searching the internet for related information I came across a Taiwanese trial that I thought could be interesting. The investigators aim to study the molecular pathogenesis of bleb formation in individuals who have sufferred a spontaneous pneumothorax. Additionally, resected blebs from these patients will be used for RNA and protein analyses (adjacent normal lung tissue will be used as a control for comparison).

Hypothetically,  individuals with undiagnosed  BHD Syndrome, could find themselves participating in this trial and I’d be interested to see if there were any difference in the underlying mechanisms of bleb formation in their lungs compared to BHD-negative cases.

Furthermore it would be interesting if the investigators could be persuaded to include a FLCN gene test as part of their trial!? More information about this trail can be found here.

Smith-Magenis Syndrome and Spontaneous Pneumothorax in BHD

A recently published paper by Truong et al (link) providing two case reports of Smith-Magenis Syndrome (SMS) patients caught my eye yesterday:

SMS is caused by deletions of 17p11.2, a chromosomal region that encompasses the retinoic induced-1 (RAI1) gene, although some cases have been found to be caused by point mutations in RAI1 itself.

SMS is characterised by ‘intellectual disabilities, sleep disturbance, behavioural problems, and a variety of craniofacial, skeletal, and visceral anomalies’. At first glance this syndrome seems unrelated to BHD Syndrome since none of the classic triad of BHD feature in SMS, however, the authors report that one cases of SMS has suffered  three incidences of spontaneous pneumothorax. This lead the authors to carry out mutational analysis of FLCN and subsequently identified the SNP c.871+36G>A. This mutation has previously been identified (Gunji et al., 2007; Cho et al., 2008; Wei et al., 2009) and has been classified a non-synonymous variant. However, alignment studies by the authors have shown that the mutation results in a missense mutation in the FLCN isoform 2.

My first impression is that this is an interesting finding, which may or may not prove to be significant since this has only been detected in a single case, but could this imply some kind of interaction of RAI1 and FLCN isoform 2 in the lungs?

Co-incidentally the article is currently free to downlaod and can be found in our BHD Article Library.

The ‘Partnership for Cures’ project

The process of identifying a suitable drug target for any given disease (inherited or otherwise) can be an extremely long process; translational research, drug discovery and clinical trials all mean that identifying and issuing a treatment can take decades and a considerable amount of money.

The ‘Partnership for Cures’ program funds drug repurposing projects enabling so-called ‘orphan diseases’ to be treated with existing therapies, foregoing the lengthy clinical trial process and massive costs, since such products have already been rigorously tested and approved.

There are currently several projects in the pipeline evaluating possible‘re-purposed’ therapies for BHD Syndrome, making this an extremely exciting time.

Coming soon: BHD Researcher Interviews is the primary online reference site for anyone interested in BHD Syndrome, but as well as providing access to information, we have also been trying to cultivate an online BHD community through our online forum.

In order to keep the BHD community informed about scientific research being carried out on BHD Syndrome, we will soon be airing video interviews with scientists at the forefront of BHD Research.

You’ll be able to learn what their groups are currently doing, how they’re doing it and what their own opinions of current research are.

As well as serving the BHD community, I think this is a great way of advertising the excellent work being carried out and could aid to bring together and inform the scientific community too!

We’re really excited about this project, so watch this space!!!

Novel Mutations

I had originally intended to blog about a novel entire exon 14 deletion in a female BHD patient that has been identified by Sempau et al, (Actas Dermosifiliogr. 2010 Sep;101(7):637-40).

However, since the article is only available in Spanish, I thought it would be prudent to wait for the English translation to be issued (which should be due in a few days according to the official website) before I analyse the matter further.

What I do think is important and springs from this paper is how vitally important it is for the BHD community to share data like this. Significantly, the Folliculin Sequence Variation Database has been established, and is actively curated so that this kind of data can be consolidated in one place, and is freely available as a resource to everyone. I would impress upon all the clinical geneticists out there carrying out BHD research to bear this in mind and submit published findings.

Developing a BHD Patient Voice

One of the more resounding messages that came out of the recent IKCC meeting (see last blog) was the power of proactive rare disease communities, and how patient advocacy groups can use this to inform new research. The benefits don’t stop there though.

We know that BHD Syndrome is rare, so very often a BHD patient may not know anyone outside of their own family who also has the syndrome. Who do you talk to about new symptoms, popular treatments, and more importantly effective treatments?

In cases like this, where individuals may be geographically isolated from each other, reaching out to another person is difficult, and there’s a distinction to be made. Sometimes you may not want to talk to your partner, or your medical doctor, but someone who is going through the same thing. In recent years the internet has made the world a much smaller space, and I’d like to use this blog to encourage people to reach out to each other. There are no stupid questions and every opinion counts.

Why not use our forum to either share your experiences or ask a question, maybe someone has the answer, maybe someone has wanted to ask the same question and is a bit reluctant to set foot onto the ‘information superhighway’!

Social metworking has really exploded recently, and we’ve developed a Facebook profile to keep up with the times! Click the link on the homepage to be ‘friends’ with us so that you can get timely updates about our activities.

1st International Conference for Organizations Representing Patients with Kidney Cancer

Last weekend the Myrovlytis Trust attended the 1st International Conference for Organizations Representing Patients with Kidney Cancer in Frankfurt, Germany.

The meeting, organised by the International Kidney Cancer Coalition, brought together a global community of patient advocacy groups, cancer survivors, clinicians and researchers to discuss how best to support individuals effected by kidney cancer.

Overall the meeting was extremely well organised and had a very interesting program. All who attended were enthusiastic and very passionate about the future of kidney cancer patients. It was great to share best practices with similar organisations and to learn how to best use the patient voice to influence clinical research at the earliest stages of design. I’d always thought that the clinical trial design and recruitment process was a rigid one and not up for debate, but now we know that an organised patient ‘voice’ will be listened to by pharmaceutical industries, or infact, that advocacy groups are willingly consulted by pharma to ensure that study design and patient recruitment is the best it can be.

The current state of therapies available to kidney cancer patients was also discussed. One topic that came up concerned the fact that most of these therapies slow down cancer progression by targetting pathways that aid tumour growth (i.e. VEGF as an anti-angiogenic target), instead of actually ‘killing’ the tumour cell itself. In relation to BHD Syndrome, I found this interesting since the majority of BHD research being carried out concerns identifying the pathogenic mechanisms that underly the disease itself, and by profiling BHD Syndrome at a molecular and biochemical level, I feel researchers will uncover drug targets that will help treat the disease and not slow down the symptoms.

To finish, I would like to commend the IKCC Steering Committee on producing an excellent meeting and to all those who attended for making the weekend a success…stay in touch!

Resource: Familial Cancer Syndromes

Familial Cancer Syndromes is a relatively new online resource that can be found here. As the title suggests it provides detailed scientific information on several  inherited syndromes, more specifically there is now a chapter on BHD Syndrome that researchers and the general public may find useful. I find it reassuring to see references to BHD Syndrome are becoming more common than say a year ago, and I feel that this can only help to increase awareness of this disease.


Last week I wrote about the possible contribution to renal tumourigenesis posed by inactivation (or deregulation) of DNA repair enzymes. Following on from that theme I found a paper by Komori et al, 2009* in Oncogene entitled ‘A novel protein, MAPO1, that functions in apoptosis triggered by O6-methylguanine mispair in DNA’. In it, the authors theorise that the protein MAPO1 may participate in the signalling cascade downstream of the DNA repair protein MGMT.

MGMT is responsible for the detection and repair of DNA damage caused by alkylating agents. If the damage is severe enough then the repair mechanism is bypassed, and to prevent transition mutations being propagated after DNA replication, apoptosis is initiated by MGMT via MAPO1, as the authors suggest.

So how is this relevant to BHD Syndrome? MAPO1 also goes by the name FNIP2. The relationship between FNIP2 and FLCN is not fully understood but could FLCN have any role in regulating FNIP2 activity in apoptosis induction in response to alkylating damage? Could this facet contribute to the accumulation of genetic instability in tissues with high cell turnover and metabolism (i.e. the kidneys) and could we speculate that this could contribute to the development of malignant tumours in the kidneys of BHD patients as opposed to any other organ since the kidneys are exposed to high levels of external chemicals due to their role in filtering urine?

Komori, K., Takagi, Y., Sanada, M., Lim, T.-H., Nakatsu, Y., Tsuzuki, T., Sekiguchi, M., Hidaka, M. A novel protein, MAPO1, that functions in apoptosis triggered by O(6)-methylguanine mispair in DNA. Oncogene 28: 1142-1150, 2009.

The role of DNA repair enzymes in BHD associated renal tumourigenesis?

The focus of scientific research into BHD Syndrome should centre on elucidating the biological role of folliculin (FLCN) within the cell, but a recent paper in the European Journal of Cancer has brought the topic of DNA repair enzymes into light.

The multi-step model for tumourigenesis proposes that the tumourigenic growth of malignant cells from normal tissue is preceded by the accumulation of genetic errors in a sequential fashion, where each step provides a positive growth advantage to the nascent tumour cells, allowing them to break free from the normal regulatory constraints that determine normal growth and differentiation. Habib et al, (2010)* have shown that rapamycin treated HK2 cells, mouse Tsc-deficient cells and human VHL-deficient cells leads to increased protein and promoter activity of the DNA repair enzyme OGG1 and that this mediated via an increase in  expression of the transcription factor, NF-YA. This increase in OGG1 activity is thought to suppress the development of further tumours in treated cells and the authors speculate that a rapamycin-mediated mechanism of enhancing DNA repair in cancer cells  may explain the inhibition of further tumourigenic growth for as long as rapamycin is applied.

DNA repair enzymes such as OGG1 repair damage to DNA bases caused by oxidative damage, which may occur because of normal aerobic metabolism or exposure to external environmental carcinogens. Whilst such damage itself is not immediately pathogenic, it results in a mutator phenotype since the ‘increasing impairment in DNA repair contributes to the genomic instability, and consequently increases the risk of cancer’. Indeed, a familial colorectal polyposis syndrome know as MAP is  caused by bialleic inactivation of the DNA repair enzyme MUTYH, so as ‘family’ of proteins, their significance in cancer aetiology is not to be underestimated.

Given the phenotypic overlap between BHD Syndrome, VHL and TSC, as well as the role implicated for FLCN in mTOR signalling (and subsequent therapeutic benefit of rapamycin analogs) I wonder whether DNA repair enzymes may have a similar role in BHD associated tumourigenesis.

*Habib SL, et al. Novel mechanism of reducing tumourigenesis: Upregulation of the DNA repair enzyme OGG1 by rapamycin-mediated AMPK activation and mTOR inhibition.Eur J Cancer. 2010 Jul 23.

Eur J Cancer. 2010 Jul 23. [Epub ahead of print]

Novel mechanism of reducing tumourigenesis: Upregulation of the DNA repair enzyme OGG1 by rapamycin-mediated AMPK activation and mTOR inhibition.

Habib SL, Kasinath BS, Arya RR, Vexler S, Velagapudi C.