“If an individual has Birt-Hogg-Dubé syndrome, then it’s very important that we’re able to diagnose it, because they and their family members may also be at risk of kidney cancer,” said Professor Marciniak, a University of Cambridge researcher. His claims are so significant that they call into question findings from a study, published first in 2009, that revolutionized our understanding of the prevalence of this FLCN gene mutation, and estimated that as many as 1 in 3,000 people have the mutation, a staggering growth from prior estimates that had that number at 1 in 200,000.
The FLCN gene, a tumor suppressor, is strongly implicated in the autosomal dominant Birt-Hogg-Dubé syndrome (BHD) syndrome, which is characterized by lung cysts, benign skin tumors and kidney cancer. The research, reported in the journal Thorax, drew on genomic data from more than 550,000 People in Britain through datasets such as the UK Biobank, the 100,000 Genomes Project and East London Genes & Health. The variant of FLCN associated with BHD occurs in about one in 2,710 to one in 4,190 individuals, the researchers found. These numbers contrast sharply with previous assumptions and indicate that genetic testing can help to identify at-risk groups.
The study by Jiang et al. made a particularly interesting observation regarding the risk association among the FLCN mutation carriers which proved to be a little more nuanced. Patients diagnosed with BHD had a lifetime risk of pneumothorax up to 37%, while this risk was lower at 28% when taking the larger carrier population into account without a clinical diagnosis of BHD. Even more striking is the disparity in the risk of developing kidney cancer only 1 percent of undiagnosed carriers develop the disease, compared with 32 percent of those with the syndrome. These results suggest that the expression of BHD-related phenotypes may be modulated by genetic and/or environmental factors.
Pneumothorax or punctured lung occurs when air escapes into the pleural space and causes painful lung collapse and shortness of breath. Spontaneous pneumothorax is most commonly seen in tall, slim young males in their teens to early twenties, but those associated with BHD are typically also correlated with tell-tale cysts, which are found in the lower lungs and can be identified from MRI scans. This distinction is critical for diagnosis, especially if the patients are outside the demographic norms for spontaneous pneumothorax.
If confirmed, these findings have implications beyond pneumothorax. That raises salient questions, like whether individuals with the malfunctioning FLCN gene should be screened for kidney cancer as a matter of routine examination. But Professor Marciniak says we should not intervene unnecessarily, saying: “Unless we see the other tell-tale signs of Birt-Hogg-Dubé syndrome, our study shows there’s no reason to believe they’ll have the same elevated cancer risk.” This perspective is consistent with the broader realization that genetic mutations alone do not determine cancer risk, but rather interact with environmental forces to influence disease outcome.
The study also provides insight into the molecular basis of BHD. FLCN and its interacting proteins FNIP1 and FNIP2 play numerous roles in cellular processes, including regulation of the mTOR pathway and mitochondrial biogenesis. They maintain cellular homeostasis in such a way and their loss may be involved in the appearance of BHD associated phenotypes. Moreover, FLCN mutations are known to disrupt cell-cell adhesion and polarity [30, 31], providing further complexity to the pathology of the syndrome.
This research was supported by the Myrovlytis Trust, a longstanding funder of data (BDH awareness) and researches. Katie Honeywood, the Trust’s Chief Executive, said: “It highlights the importance of genetic testing for anyone who has any of the main symptoms associated with BHD including a collapsed lung. And even more so the importance of the medical world being aware of this condition for anyone who presents at an emergency department or clinic with these symptoms.” he said.
These findings also reflect broader discussions in the medical community about the role of genetic testing in clinical practice. With the evolution of genetic modalities, detection of carriers for mutations like FLCN is going to become only easier, and certainly with it, improved upon. The actual challenge is how to translate that genetic understanding into health care plans. For instance, presentation of a pathogenic FLCN variant may impact pneumothorax management and the need for kidney cancer surveillance, but ethical dilemmas arise with psychosocial implications following knowledge of genetic risks.
This investigation into a wide ranging population genomic dataset further demonstrates the effectiveness of this form of genomics in exposing found but not previously documented information of the local and global distribution of diseases. It calls for collaborative networks, such as those like the UK’s Familial Pneumothorax Rare Disease Collaborative Network, which is co-led by Professor Marciniak and Professor Kevin Blyth, to offer the greatest support for patients with rare genetic disorders. The positive, as Professor Marciniak correctly pointed out, is that “The good news is that the punctured lung usually happens 10 to 20 years before the individual shows symptoms of kidney cancer, so we can keep an eye on them, screen them every year, and if we see the tumor it should still be early enough to cure it.”
[The road to the next discoveries about BHD and its perils wasn’t a smooth one. This has been constrained by historical (ie, pre-genomic) paradigms of disease inheritance and is being confounded by the drive to identify disease-specific definitive mutations, but future studies must address the genetic and environmental modifiers of the expressivity of FLCN mutations. igenetic studies that assess populations across different cohorts may also help further clarify how BHD-associated phenotypes vary in penetrance. For now, the results provide an important reminder that genetic disorders can be complex, and that doctors must avoid taking a one-size-fits-all approach to diagnosing and treating them.
The accompanying study makes a compelling argument to clinicians and geneticists that there is a need to incorporate genetic data into clinical decision-making. This highlights how crucial it is to continue educating and raising awareness about rare genetic disorders like BHD that can greatly influence future patient management and family health trajectories despite being rare. The results of this and similar studies will certainly play an important role in the age of personalized medicine, as scientists gradually read the mysterious text contained in the entire genome.
More on this study can be viewed in Cambridge’s research results and analysis of population-based prevalence. Explore BHD-related risks from clinical perspectives.
