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Biallelic NF1 inactivation in high grade serous ovarian cancers from patients with neurofibromatosis type 1


Neurofibromatosis type 1 (NF1) is a multisystem disorder caused by germline heterozygous NF1 loss-of-function variants. The NF1 gene encodes neurofibromin, a RAS GTPase-activating protein, which functions by down-regulating RAS/RAF/MAPK-signalling pathways. Somatic NF1 aberrations frequently occur in sporadic ovarian cancer (OC), but the incidence of OC in NF1 patients is rare. Here we report the germline and somatic findings for two unrelated patients with NF1 and high-grade serous OC. Germline testing revealed a heterozygous NF1 pathogenic variant in each patient, c.7096_7101del (p.Asn2366_Phe2367del) and c.964delA (p.Ile322Leufs*54), respectively. No germline variants in well-established OC predisposition genes were detected, including BRCA1 and BRCA2. Tumor loss-of-heterozygosity analysis demonstrated loss of the wild type NF1 allele for both patients. Biallelic NF1 inactivation occurs as part of OC pathogenesis in NF1 patients. Although the penetrance of NF1-associated OC is insufficient to warrant risk-reducing interventions, our findings highlight the potential for therapies targeting the RAS/RAF/MAPK-signalling pathway for these cases.

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The authors would like to thank Ms Xinyi Loh, Medical Technologist of the Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, for extracting the tumor DNA samples. We express our gratitude to the Lee foundation for their generous donations to the Lee Kong Chian NCCS Cancer Genetics Service fund that help subsidize the cost of testing for our patients in need. We thank the doctors for referring their patients and collaborating with us. Most importantly, we would like to thank the patients involved for their willingness to partake in research.


J.N is funded by the National Research Council Singapore Clinician-Scientist Award (NMRC/CSAINV/0017/2017). Additional funding was provided by the National Research Foundation Singapore under its NMRC Centre Grant Programme (NMRC-CG-RIE 2020 - Project No. NMRC/CG/M003/2017). AstraZeneca provided funding for ovarian cancer research.

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Correspondence to Joanne Ngeow.

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Conflict of Interest

J.N. received funding from AstraZeneca for breast and ovarian cancer research. The remaining authors have no conflict of interest to declare.

Informed consent

The research was approved by the SingHealth Centralised Institutional Review Board (CIRB number is 2011/826/B) and was performed in accordance with the Helsinki Declaration of 1975, as revised in 2000. Written informed consent for research was obtained from both patients.

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Courtney, E., Chan, S.H., Li, S.T. et al. Biallelic NF1 inactivation in high grade serous ovarian cancers from patients with neurofibromatosis type 1. Familial Cancer 19, 353–358 (2020).

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  • Neurofibromatosis
  • NF1
  • Neurofibromin
  • Ovarian
  • Cancer