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.

中文翻译：

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双等位基因NF1在1型神经纤维瘤病患者的高度浆液性卵巢癌中失活。

1型神经纤维瘤病（NF1）是由种系杂合性NF1功能丧失变异体引起的多系统疾病。的NF1基因编码神经纤维瘤蛋白，一个RAS GTP酶激活蛋白，其功能通过下调RAS / RAF / MAPK信号途径。体细胞NF1畸变经常发生在散发性卵巢癌（OC）中，但是NF1患者中OC的发生率很少。在这里，我们报告了两名不相关的NF1和高级别浆液性OC患者的种系和体细胞发现。胚芽测试显示杂合NF1每个患者的病原体变异分别为c.7096_7101del（p.Asn2366_Phe2367del）和c.964delA（p.Ile322Leufs * 54）。未检测到成熟的OC易感基因中的种系变体，包括BRCA1和BRCA2。肿瘤杂合性丧失分析表明，两名患者均丧失了野生型NF1等位基因。双等位基因NF1失活是NF1患者OC发病机制的一部分。尽管与NF1相关的OC的渗透性不足以保证降低风险的干预措施，但我们的研究结果突显了针对RAS / RAF / MAPK信号通路的疗法的潜力。