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首页> 外文期刊>Gynecologic Oncology Reports >Clonal lineage of high grade serous ovarian cancer in a patient with neurofibromatosis type 1
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Clonal lineage of high grade serous ovarian cancer in a patient with neurofibromatosis type 1

机译：1型神经纤维瘤病患者的高级浆液性卵巢癌的克隆谱系

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Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene encoding neurofibromin, which negatively regulates Ras signaling. NF1 patients have an increased risk of developing early onset breast cancer, however, the association between NF1 and high grade serous ovarian cancer (HGSOC) is unclear. Since most NF1-related tumors exhibit early biallelic inactivation of NF1 , we evaluated the evolution of genetic alterations in HGSOC in an NF1 patient. Somatic variation analysis of whole exome sequencing of tumor samples from both ovaries and a peritoneal metastasis showed a clonal lineage originating from an ancestral clone within the left adnexa, which exhibited copy number (CN) loss of heterozygosity (LOH) in the region of chromosome 17 containing TP53, NF1 , and BRC A1 and mutation of the other TP53 allele. This event led to biallelic inactivation of NF1 and TP53 and LOH for the BRCA1 germline mutation. Subsequent CN alterations were found in the dominant tumor clone in the left ovary and nearly 100% of tumor at other sites. Neurofibromin modeling studies suggested that the germline NF1 mutation could potentially alter protein function. These results demonstrate early, biallelic inactivation of neurofibromin in HGSOC and highlight the potential of targeting RAS signaling in NF1 patients. Highlights ? A link between neurofibromatosis type 1 and ovarian cancer has emerged. ? A genetic study of high grade serous ovarian cancer in a patient with NF1 is presented. ? Biallelic inactivation of the NF1 gene is an early event in HGSOC tumorigenesis. ? The NF1 pathway is a potential therapeutic target in women with NF1 that develop HGSOC.
机译：1型神经纤维瘤病（NF1）是由编码神经纤维蛋白的NF1基因突变引起的，该突变负调控Ras信号传导。 NF1患者罹患早期乳腺癌的风险增加，但是，NF1与高级别浆液性卵巢癌（HGSOC）之间的关联尚不清楚。由于大多数与NF1相关的肿瘤均表现出NF1的早期双等位基因失活，因此我们评估了NF1患者中HGSOC基因改变的演变。卵巢和腹膜转移肿瘤样本的全外显子组测序的体细胞变异分析显示，克隆谱系起源于左附件内的祖先克隆，在第17号染色​​体区域表现出杂合度（LOH）的拷贝数（CN）丧失。含有TP53，NF1和BRC A1以及其他TP53等位基因的突变。该事件导致针对BRCA1种系突变的NF1和TP53和LOH的双等位基因失活。随后在左卵巢的显性肿瘤克隆中发现了CN改变，其他部位的肿瘤接近100％。神经纤维蛋白建模研究表明，种系NF1突变可能潜在地改变蛋白质功能。这些结果证明了HGSOC中神经纤维蛋白的早期双等位基因失活，并突出了NF1患者靶向RAS信号的潜力。强调 ？已经出现了1型神经纤维瘤病与卵巢癌之间的联系。 ？提出了对患有NF1的高级别浆液性卵巢癌的基因研究。 ？ NF1基因的双等位基因失活是HGSOC肿瘤发生中的早期事件。 ？ NF1途径是发展为HGSOC的NF1女性的潜在治疗靶点。

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