Shi Eileen, Chmielecki Juliann, Tang Chih-Min, Wang Kai, Heinrich Michael C, Kang Guhyun, Corless Christopher L, Hong David, Fero Katherine E, Murphy James D, Fanta Paul T, Ali Siraj M, De Siena Martina, Burgoyne Adam M, Movva Sujana, Madlensky Lisa, Heestand Gregory M, Trent Jonathan C, Kurzrock Razelle, Morosini Deborah, Ross Jeffrey S, Harismendy Olivier, Sicklick Jason K
School of Medicine, University of California San Diego, La Jolla, CA, USA.
Foundation Medicine, Inc., Cambridge, MA, USA.
J Transl Med. 2016 Dec 14;14(1):339. doi: 10.1186/s12967-016-1075-6.
About 10-15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies.
We performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess for their somatic alterations.
We identified 24 GIST lacking alterations in the canonical KIT/PDGFRA/RAS pathways, including 12 without SDHx alterations. These 24 patients were mostly adults (96%). The tumors had a 46% rate of nodal metastases. These 24 GIST were more commonly mutated at 7 genes: ARID1B, ATR, FGFR1, LTK, SUFU, PARK2 and ZNF217. Two tumors harbored FGFR1 gene fusions (FGFR1-HOOK3, FGFR1-TACC1) and one harbored an ETV6-NTRK3 fusion that responded to TRK inhibition. In an independent sample set, we identified 5 GIST cases lacking alterations in the KIT/PDGFRA/SDHx/RAS pathways, including two additional cases with FGFR1-TACC1 and ETV6-NTRK3 fusions.
Using patient demographics, tumor characteristics, and CGP, we show that GIST lacking alterations in canonical genes occur in younger patients, frequently metastasize to lymph nodes, and most contain deleterious genomic alterations, including gene fusions involving FGFR1 and NTRK3. If confirmed in larger series, routine testing for these translocations may be indicated for this subset of GIST. Moreover, these findings can be used to guide personalized treatments for patients with GIST. Trial registration NCT 02576431. Registered October 12, 2015.
约10%-15%的成人胃肠道间质瘤（GIST）以及大多数儿童GIST在KIT、血小板衍生生长因子受体α（PDGFRA）、琥珀酸脱氢酶亚基（SDHx）或RAS通路成分（KRAS、BRAF、神经纤维瘤病1型基因（NF1））中不存在突变。在这一罕见肿瘤亚群中鉴定其他突变基因对于识别改变的生物学通路和选择靶向治疗具有重要的临床意义。
我们对186例GIST的300多个癌症相关基因的编码区进行了全面基因组分析（CGP），以评估其体细胞改变。
我们鉴定出24例GIST在经典的KIT/PDGFRA/RAS通路中无改变，其中12例无SDHx改变。这24例患者大多为成年人（96%）。这些肿瘤的淋巴结转移率为46%。这24例GIST在7个基因中更常见发生突变：AT丰富区结合蛋白1B（ARID1B）、共济失调毛细血管扩张症突变基因（ATR）、成纤维细胞生长因子受体1（FGFR1）、白细胞酪氨酸激酶（LTK）、Suppressor of fused homolog（SUFU）、帕金森病相关蛋白2（PARK2）和锌指蛋白217（ZNF217）。2例肿瘤存在FGFR1基因融合（FGFR1-HOOK3、FGFR1-TACC1），1例存在ETV6-NTRK3融合，对TRK抑制有反应。在一个独立样本集中，我们鉴定出5例GIST病例在KIT/PDGFRA/SDHx/RAS通路中无改变，包括另外2例FGFR1-TACC1和ETV6-NTRK3融合病例。
利用患者人口统计学特征、肿瘤特征和CGP，我们发现经典基因无改变的GIST发生在较年轻患者中，常转移至淋巴结，且大多含有有害的基因组改变，包括涉及FGFR1和NTRK3的基因融合。如果在更大系列研究中得到证实，对于这一GIST亚群可能需要常规检测这些易位。此外，这些发现可用于指导GIST患者的个性化治疗。试验注册号NCT 02576431。于2015年10月12日注册。
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