Biallelic NF1 inactivation in high grade serous ovarian cancers from patients with neurofibromatosis type 1
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SHORT COMMUNICATION
Biallelic NF1 inactivation in high grade serous ovarian cancers from patients with neurofibromatosis type 1 Eliza Courtney1 · Sock Hoai Chan1 · Shao Tzu Li1 · Diana Ishak1 · Khurshid Merchant2 · Tarryn Shaw1 · Wen Yee Chay3 · Felicia Hui Xian Chin3 · Wai Loong Wong3 · Adele Wong2 · Joanne Ngeow1,4
© Springer Nature B.V. 2020
Abstract 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. Keywords Neurofibromatosis · NF1 · Neurofibromin · Ovarian · Cancer
Introduction Neurofibromatosis type 1 (NF1; MIM# 162200) is a common autosomal dominant multisystem disorder, with a birth incidence of approximately 1/2000-1/3000 [1, 2]. Individuals with NF1 are at increased risk for a range of benign and malignant tumors, skeletal abnormalities, and cognitive Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10689-020-00184-3) contains supplementary material, which is available to authorized users. * Joanne Ngeow [email protected] 1
Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore
2
Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore 229899, Singapore
3
KK Gynaecological Cancer Centre, KK Women’s and Children’s Hospital, Singapore 229899, Singapore
4
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
deficits [3]. Other characteristic physical features include café-au-lait macules (CALMs), lisch nodules, and freckling of the axillary, inguinal, and choroidal regions. Cutaneous neurofibromas occur in almost all individuals with NF1 [3–5]. Registry-based studies have demonstrated the presence of plexiform neurofibromas in approximately 15–30% of individuals with NF1 [4, 6–9], although imaging-based studies report a higher prevalence of 40–60% [10–13]. Malignant peripheral nerve sheath tumors (
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