Although guidelines recommend BRcA testing for all women with non-mucinous epithelial ovarian cancer, there is significant variability in access to testing across the UK. A germline BRCA mutation (BRCAm) in ovarian cancer patients provides prognostic and predictive information and influences clinical management, such as the use of pARp inhibitors, which have demonstrated a progression-free survival benefit in the BRCAm cohort. Additionally, the finding of a BRCAm has significant implications for patients and their families in terms of cancer risk and prevention. We studied the impact of a newlyformed, oncologist-led 'mainstreaming' germline BRCA testing pathway in 255 ovarian cancer patients at Imperial College NHS Trust. Prior to the establishment of 'mainstreaming', uptake of germline BRCA testing was 14% with a mean turnaround time of 148.2 calendar days. The 'mainstreaming' approach led to a 95% uptake of germline BRCA testing and a mean turnaround time of 20.6 days. Thirty-four (13.33%) BRCAm patients were identified. At the time of data collection nine BRCAm patients had received a PARP inhibitor off-trial, three had entered a PARP inhibitor trial and 5 were receiving platinum-based chemotherapy with a plan to receive PARP inhibitor maintenance. This study provides further evidence of the impact of oncologist-led 'mainstreaming' programs. Uptake and utility of mainstreaming pathway. There was a 95% uptake of BRCA testing via the Scientific RepoRtS | (2020) 10:3390 | https://doi.

Noonan Syndrome (NS) is a genetic condition, known to be associated with low grade central nervous system tumours in children but only very rarely associated with high-grade gliomas. Here we describe the first reported case of a spinal high-grade astrocytoma with piloid features (HGAP) in a child with NS. This case presented as a diagnostic and treatment dilemma, prior to comprehensive molecular profiling with whole-genome germline and tumour sequencing, tumour transcriptome sequencing and DNA methylation analysis. The methylation profile was a strong match for HGAP and was critical to establish this child’s diagnosis, as this is an essential diagnostic criteria for confirmation of this relatively new tumour group. Sequencing results identified activation of the MAPK signalling pathway with somatic variants in FGFR1 and NF1 and the previously known germline pathogenic variant in PTPN11. The somatic molecular profile was consistent with those previously reported in other HGAP case series and reports, whereas the germline finding has not been previously described in individuals with this tumour type. This patient’s molecular profile adds to the small group of paediatric cases reported in the literature, continuing to expand our understanding of this new WHO diagnostic category. Confirmation of this rare diagnosis was critical to this child’s management and targetable aberrations were identified, providing alternative therapeutic options. The therapeutic targets included known drivers within the MAPK pathway, but also changes not previously associated with HGAP such as differential expression of VEGFA and PD-L1. Together this case underscores the power of precision medicine from a diagnostic, therapeutic and clinical management perspective, and describes an association between HGAP and NS which has not previously been reported.