A highlights summary of current global research particularly recent presentations at the NF Conference in Scottsdale, Arizona.

These tumours shed small amounts of their DNA into the patient’s bloodstream. Unlike solid tumours which are often hidden deep within a patient’s body, accessing the blood is easy and safe. Therefore, liquid biopsy - a simple blood test offering a non-invasive alternative to tissue biopsy - gives us an opportunity to detect cancer. 

Loss-of-function of the epigenetic PRC2 complex due to mutations in its core components SUZ12 or EED, is a hallmark for the transition of plexiform neurofibromas (pNF) to Malignant Peripheral Nerve Sheath Tumor (MPNST), and results in an altered DNA methylation landscape for these lesions.

This study seeks to identify DNA methylation biomarkers of MPNST, for the purpose of generating a liquid biopsy test for MPNST in NF1, in order to aid/improve the diagnosis of MPNST. DNA methylation datasets of pNF and MPNST were interrogated to identify differentially methylated regions (DMRs), and further filtering was applied based on methylation levels in blood and normal tissues known to contribute DNA to the blood, to select for DMRs suitable for MPNST classification in liquid biopsy (LB-DMRs).

LB-DMRs were combined into a signature for MPNST detection and evaluated on the bulk tissue sets to record 91-100% sensitivity and 95-100% specificity.

Neurofibromin (NF1) mutations cause NF1 and drive numerous cancers, including breast and brain tumours. NF1 inhibits cellular proliferation through its guanosine triphosphatase-activating protein activity against the Ras oncogene. 

We recently solved the cryo-EM structure of the full-length 640-kDa NF1 homodimer captured with the catalytic GAP-related domain and lipid-binding SEC-PH domains positioned against the core scaffold in a closed, autoinhibited conformation. 

Our structural data have allowed us to map the location of disease-associated NF1 variants across the NF1 structure. 

Using a combination of biophysical studies, BRET, and FRET biosensors, we are now capturing the effect of NF1-disease-associated mutations on Ras signalling in live cells. These data allow us to directly quantify the effect of NF1 disease-associated mutations on Ras activity in space (cell location) and time (kinetics) and will allow us to link NF1-regulation of Ras activity to changes in cell growth and proliferation.

In addition, these data highlight protein regions that are more sensitive to mutagenesis and may link mutations in some protein regions to differential effects on Ras signalling. These studies begin to provide a long-sought-after structural explanation for the extreme susceptibility of the molecule to loss-of-function mutations.

The research team has been actively working to develop gene therapy vectors aimed at treating individuals with NF before the onset of symptoms, including tumour formation. This therapeutic approach could be likened to a "cancer vaccine" in certain respects – it seeks to target a patient’s genes to prevent future disease. 

This presentation will focus on the potential of CRISPR/Cas gene editing to correct underlying gene mutations causative for NF and adeno-associated viral vectors (AAV vectors) that will facilitate therapeutic delivery. 

Discussion on session 1