PO-102 Understanding the role of the tumour suppressor, FLCN, in renal tumorigenesis

Abstract

IntroductionOur basic understanding of renal cell carcinoma (RRC) in the general population is limited. To gain a better understanding of how RRC develops, I took advantage of a genetic model of kidney cancer that mirrors a genetic disease called Birt-Hogg-Dubé (BHD) syndrome. BHD patients have an increased risk of developing kidney cancer, and unlike other genetic disorders with a predisposition to RRC, BHD patients are prone to all tumour subtypes. These patients are born with inactivating mutations within a gene called Folliculin (FLCN), a tumour suppressor protein of unknown function that could be involved in monitoring DNA damage.Material and methodsTo better define the tumour suppressor role of FLCN, I carried out a protein-protein interaction using FLCN as bait, which revealed that FLCN interacts with the DNA-damage response machinery. To further explore FLCN involvement in DNA damage, I used RNAi to generated FLCN knockdown in human proximal tubule kidney cells – which are thought to be the origin cells of BHD associated renal tumours – and performed basic cellular experiment such as western blot and flow cytometry.Results and discussionsI discovered that FLCN interacts with DNA-PKcs, a DNA damage component that is responsible for repairing double strand DNA (dsDNA) breaks. This is an important advancement, as it now implicates FLCN in the maintenance of DNA. The association of FLCN with DNA-PKcs weakens when cells are subjected to DNA damage. As a consequence of FLCN loss of function, kidney cells accumulate DNA damage and the activity of DNA damage response pathways are elevated. I also have evidence showing that a perturbed G1/S check point in FLCN-deficient cells which is a known driver of cancer progression.ConclusionUltimately, my work highlights a novel role of FLCN within renal cell tumourgenesis, suggesting it functions to prevent genomic instability. Genetic conditions, such as BHD that predispose individuals to cancer, while rare themselves, provide valuable insight into somatic tumour development. By using BHD syndrome as a model of genetic instability, further work will be carried out to mechanistically establish FLCN’s role in DNA integrity and will provide valuable insight into sporadic renal cancer within the general population.