Introduction/Background NF1 protein loss results in hyperactivity of the mitogen-activated protein kinase (MAPK) pathway in cancer. NF1 copy number loss (NF1-CNL) has been identified as a frequent event in high-grade serous ovarian carcinoma (HGSOC), alongside other common molecular aberrations (TP53, BRCA1, and BRCA2 mutation; CCNE1 copy number gain and EMSY overexpression; RB1 and PTEN protein loss). The molecular context and prognostic consequence of NF1-CNL in HGSOC requires investigation.

Methodology NF1-CNL cases were identified from uniformly analysed in-house (N = 81) and publicly-available (N = 124) whole genome sequencing data of HGSOCs. Homologous recombination deficiency (HRD) status was designated by HRDetect Score. NF1 mRNA expression and MAPK Pathway Activity Score (MPAS) were quantified using RNA sequencing data (N = 149). Progression-free and overall survival were defined as the interval between diagnosis and first radiologically-identified recurrence or death, respectively. R version 4.2.2. was used to conduct Mann-Whitney U tests, calculate odds ratios, and fit Cox proportional hazards models.

Results NF1-CNL was identified in 46/205 cases (22.4%). NF1-CNL tumours demonstrated lower NF1 mRNA expression levels and higher MPAS than non NF1-CNL tumours (P = 0.008 and 0.013, respectively). NF1-CNL events were highly enriched in the BRCA1/2-mutated (OR = 4.25, 95% CI [2.09, 8.72]) and the HRD subpopulations (OR = 9.7, 95% CI [3.68, 34.2]). Within the HRD subgroup, NF1-CNL cases experienced shorter overall survival than non NF1-CNL cases (multivariable-HR = 1.86, P = 0.029).

Conclusion NF1-CNL occurs at an appreciable frequency in HGSOC and is associated with reduced NF1 mRNA expression and increased MAPK pathway activity. NF1-CNL events are highly enriched in BRCA1/2m and HRD cases. Patients with HRD tumours and NF1-CNL events experience shorter overall survival.

Disclosures Funded by Cancer Research UK.