Li Jiaxin, Sun Lin, Liu Shasha, Liu Huimin, Li Bin, Zhan Hongjie, Sun Yan
Department of Pathology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin 300060, People's Republic of China.
Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin 300060, People's Republic of China.
Oncologist. 2025 May 8;30(5). doi: 10.1093/oncolo/oyaf110.
Although there have been multiple lines of drugs for gastrointestinal stromal tumors (GISTs), the drug response depends on the progressive tumors' biological behaviors and secondary mutations.
We investigated the primary and secondary mutations in multiple tumors from the same patients and at multiple regions from the same tumor to analyze the inter- and intratumoral heterogeneities using Sanger sequencing and next-generation sequencing (NGS).
Secondary mutations were more frequently detected in patients with a targeted therapy history and who continued their targeted therapy until surgery or biopsy, in larger tumors, and in tumors located in the intestine, abdominal cavity, and mesentery. Secondary mutations were detected in only 57.5% of the samples from the cases with secondary mutations, and 34.8% of the cases presented multiple types of secondary mutations, including both intertumoral and intratumoral heterogeneities. Temporal heterogeneity was also observed at different time points of progression. The results of NGS and Sanger sequencing were consistent for the individual sample, but Sanger sequencing detected multiple types of secondary mutations from different tumors of the same patient. Liquid biopsy also only detected partial secondary mutations revealed by Sanger sequencing.
Progressive GISTs had intertumoral and intratumoral heterogeneities of secondary mutations. Sanger sequencing had its own advantage in revealing the heterogeneity of secondary mutations. The improvement in the detection rate of secondary mutations by selecting the appropriate tumor sample to be tested, or even the appropriate tumor region or test method, is helpful to identify the optimal drugs for progressive GISTs.
尽管已有多种用于胃肠道间质瘤（GIST）的药物，但药物反应取决于进展性肿瘤的生物学行为和继发性突变。
我们使用桑格测序和二代测序（NGS）研究了同一患者多个肿瘤以及同一肿瘤多个区域的原发性和继发性突变，以分析肿瘤间和肿瘤内的异质性。
在有靶向治疗史且持续接受靶向治疗直至手术或活检的患者、较大肿瘤以及位于肠道、腹腔和肠系膜的肿瘤中，更频繁地检测到继发性突变。在有继发性突变的病例中，仅57.5%的样本检测到继发性突变，34.8%的病例呈现多种类型的继发性突变，包括肿瘤间和肿瘤内的异质性。在进展的不同时间点也观察到时间异质性。对于单个样本，NGS和桑格测序的结果一致，但桑格测序从同一患者的不同肿瘤中检测到多种类型的继发性突变。液体活检也仅检测到桑格测序揭示的部分继发性突变。
进展性GIST存在肿瘤间和肿瘤内继发性突变的异质性。桑格测序在揭示继发性突变的异质性方面有其自身优势。通过选择合适的肿瘤样本进行检测，甚至合适的肿瘤区域或检测方法来提高继发性突变的检测率，有助于为进展性GIST确定最佳药物。
