Endocr Pract. 2019 Jun;25(6):580-588. doi: 10.4158/EP-2018-0603. Epub 2019 Mar 13.
To report the rate of candidate actionable somatic mutations in patients with locally advanced and metastatic gastro-enteropancreatic (GEP) neuroendocrine tumors (NET) and of other genetic alterations that may be associated with tumorigenesis. A phase II mutation targeted therapy trial was conducted in patients with advanced well-differentiated G1/G2 GEP-NET. Mutations found in the mTOR pathway-associated genes led to treatment with the mTOR inhibitor everolimus, and were defined as actionable. Tumor deoxyribonucleic acid (DNA) from GEP-NET were sequenced and compared with germline DNA, using the OncoVAR-NET assay, designed for hybrid capture sequencing of 500 tumor suppressor genes and oncogenes. Somatic variants were called and copy-number (CN) variant analysis was performed. Thirty patients (14 small-intestine, 8 pancreatic, 3 unknown primary NET, and 5 of other primary sites) harbored 37 lesions (4 patients had DNA of multiple lesions sequenced). Only 2 patients with sporadic NET (n = 26) had an actionable mutation leading to treatment with everolimus. Driver somatic mutations were detected in 18 of 30 patients (21/37 lesions sequenced). In the remaining samples without a driver mutation, CN alterations were found in 11/16 tumors (10/12 patients), including CN loss of chromosome (Chr) 18 (<.05), CN gain of Chr 5, and loss of Chr 13. CN losses in Chr 18 were more common in patients without driver mutations detected. Pronounced genetic heterogeneity was detected in patients with multiple lesions sequenced. Genome-wide DNA sequencing may identify candidate actionable genes and lead to the identification of novel target genes for advanced well-differentiated GEP-NET. = chromosome; = copy number; = deoxyribonucleic acid; = Food and Drug Administration; = gastro-enteropancreatic; = multiple endocrine neoplasia syndrome type 1; = mammalian target of rapamycin; = neuroendocrine tumor; = progression-free survival; = pancreatic neuroendocrine tumors; = small-intestine neuroendocrine tumor.
报告局部晚期和转移性胃肠胰（GEP）神经内分泌肿瘤（NET）患者候选可操作体细胞突变的发生率和可能与肿瘤发生相关的其他遗传改变。对晚期高分化 G1/G2 GEP-NET 患者进行了 II 期突变靶向治疗试验。在 mTOR 通路相关基因中发现的突变导致使用 mTOR 抑制剂依维莫司治疗，并被定义为可操作。使用 OncoVAR-NET 测定法对 GEP-NET 的脱氧核糖核酸（DNA）进行测序，并与种系 DNA 进行比较，该测定法设计用于 500 个肿瘤抑制基因和致癌基因的杂交捕获测序。对体细胞变体进行了调用并进行了拷贝数（CN）变体分析。30 名患者（14 名小肠，8 名胰腺，3 名未知原发 NET 和 5 名其他原发部位）存在 37 个病变（4 名患者的多个病变 DNA 进行了测序）。只有 2 名散发性 NET 患者（n = 26）具有导致依维莫司治疗的可操作突变。在 30 名患者中的 18 名（测序的 37 个病变中的 21 个）中检测到驱动体细胞突变。在没有驱动突变的其余样本中，在 16 个肿瘤中的 11 个（12 名患者中的 10 个）中发现了 CN 改变，包括染色体 18（<.05）的 CN 缺失、染色体 5 的 CN 增益和染色体 13 的 CN 缺失。在未检测到驱动突变的患者中，染色体 18 的 CN 缺失更为常见。在进行了多个病变测序的患者中检测到明显的遗传异质性。全基因组 DNA 测序可鉴定候选可操作基因，并为晚期高分化 GEP-NET 鉴定新的靶基因。
