Burgoyne Adam M, De Siena Martina, Alkhuziem Maha, Tang Chih-Min, Medina Benjamin, Fanta Paul T, Belinsky Martin G, von Mehren Margaret, Thorson John A, Madlensky Lisa, Bowler Timothy, D'Angelo Francesco, Stupack Dwayne G, Harismendy Olivier, DeMatteo Ronald P, Sicklick Jason K
University of California, San Diego, La Jolla, CA.
University of California, San Diego, La Jolla, CA; Sapienza e Università di Roma, Rome, Italy.
JCO Precis Oncol. 2017;2017. doi: 10.1200/PO.17.00014. Epub 2017 Aug 15.
GI stromal tumors (GISTs) are commonly associated with somatic mutations in and . However, a subset arises from mutations in , most commonly associated with neurofibromatosis type 1. We define the anatomic distribution of alterations in GIST.
We describe the demographic/clinicopathologic features of 177 patients from two institutions whose GISTs underwent next-generation sequencing of ≥315 cancer-related genes.
We initially identified six (9.7%) of 62 GISTs with genomic alterations from the first cohort. Of these six patients, five (83.3%) had unifocal tumors at the duodenal-jejunal flexure (DJF). Two additional patients with DJF GISTs had non- ( and ) genomic alterations. After excluding one DJF GIST with an single nucleotide polymorphism, four (57.1%) of seven sequenced DJF tumors demonstrated deleterious alterations, whereas only one (1.8%) of 55 sequenced non-DJF GISTs had a deleterious somatic mutation ( < .001). One patient with DJF GIST had a germline variant that was associated with incomplete penetrance of clinical neurofibromatosis type 1 features along with a somatic mutation. Of the five DJF GISTs with any alteration, three (60%) had mutations, and three (60%) had Notch pathway mutations (, , ). We validated these findings in a second cohort of 115 GISTs, where two (40%) of five unifocal -mutated GISTs arose at the DJF, and one of these also had a Notch pathway mutation ().
Broad genomic profiling of adult GISTs has revealed that alterations are enriched in DJF GISTs. These tumors also may harbor concurrent activating and/or inactivating Notch pathway mutations. In some cases, germline genetic testing may be appropriate for patients with DJF GISTs.
胃肠道间质瘤（GIST）通常与 和 的体细胞突变相关。然而，一部分GIST起源于 的突变，最常见于1型神经纤维瘤病。我们定义了GIST中 改变的解剖分布。
我们描述了来自两个机构的177例患者的人口统计学/临床病理特征，这些患者的GIST接受了≥315个癌症相关基因的二代测序。
我们最初在第一个队列的62例GIST中鉴定出6例（9.7%）存在 基因组改变。在这6例患者中，5例（83.3%）在十二指肠-空肠曲（DJF）处有单灶性肿瘤。另外2例DJF GIST患者有非 （ 和 ）基因组改变。在排除1例具有 单核苷酸多态性的DJF GIST后，7例测序的DJF肿瘤中有4例（57.1%）显示有害的 改变，而55例测序的非DJF GIST中只有1例（1.8%）有有害的 体细胞突变（P <.001）。1例DJF GIST患者有一个种系 变异，与临床1型神经纤维瘤病特征的不完全外显率以及一个体细胞 突变相关。在5例有任何 改变的DJF GIST中，3例（60%）有 突变，3例（60%）有Notch通路突变（ 、 、 ）。我们在第二个115例GIST队列中验证了这些发现，其中5例单灶性 突变的GIST中有2例（40%）发生在DJF处，其中1例也有Notch通路突变（ ）。
成人GIST的广泛基因组分析显示， 改变在DJF GIST中富集。这些肿瘤也可能同时存在激活的 和/或失活的Notch通路突变。在某些情况下，种系 基因检测可能适用于DJF GIST患者。
