Deland Lily, Keane Simon, Olsson Bontell Thomas, Sjöberg Bexelius Tomas, Gudinaviciene Inga, De La Cuesta Esther, De Luca Francesca, Nilsson Jonas A, Carén Helena, Mörse Helena, Abel Frida
Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden.
Oncologist. 2025 Mar 10;30(3). doi: 10.1093/oncolo/oyae254.
The outcome of pilocytic astrocytoma (PA) depends heavily on the success of surgery. In cases where surgery alone is not curative, genetic analysis can be used to identify treatment targets for precision medicine. Here, we report a pediatric PA case that underwent incomplete surgical resection due to the tumor location. Clinical routine analyses demonstrated that the tumor did not carry any BRAF alteration. After postoperative surveillance, according to the low-grade glioma (LGG) protocol, recurrent tumor progressions resulted in multiple chemotherapy regimens. Screening formalin-fixed paraffin-embedded tumor material using an open-ended RNA sequencing panel revealed a novel in-frame autophagy related 16 like 1-neurotrophic receptor tyrosine kinase 2 (ATG16L1::NTRK2) fusion gene. The NTRK2 rearrangement was subsequently confirmed by fluorescent in situ hybridization on tumor tissue sections. Functional validation was performed by in vitro transient transfection of HEK293 cells and showed the ATG16L1::TRKB fusion protein to activate both the mitogen-activated protein kinase pathway and the phosphoinositide 3-kinase oncogenic pathways through increased phosphorylation of extracellular signal-regulated kinase, AKT, and S6. As a result of the identification of the NTRK fusion, the patient was enrolled in a phase I/II clinical trial of the highly selective TRK inhibitor larotrectinib. The patient responded well without significant side effects, and 8 months after the start of treatment, the contrast-enhancing tumor lesions were no longer detectable, consistent with a complete response as per Response Assessment in Neuro-Oncology (RANO) criteria. Presently, after 22 months of treatment, the patient's complete remission is sustained. Our findings highlight the importance of screening for other oncogenic drivers in BRAF-negative LGGs since rare fusion genes may serve as targets for precision oncology therapy.
毛细胞型星形细胞瘤（PA）的预后在很大程度上取决于手术的成功与否。在仅手术无法治愈的情况下，基因分析可用于确定精准医学的治疗靶点。在此，我们报告一例儿科PA病例，该病例因肿瘤位置原因接受了不完全手术切除。临床常规分析表明，肿瘤未携带任何BRAF改变。术后按照低级别胶质瘤（LGG）方案进行监测，复发性肿瘤进展导致采用了多种化疗方案。使用开放式RNA测序panel对福尔马林固定石蜡包埋的肿瘤材料进行筛查，发现了一种新的框内自噬相关16样1-神经营养受体酪氨酸激酶2（ATG16L1::NTRK2）融合基因。随后通过肿瘤组织切片的荧光原位杂交证实了NTRK2重排。通过对HEK293细胞进行体外瞬时转染进行功能验证，结果显示ATG16L1::TRKB融合蛋白通过增加细胞外信号调节激酶、AKT和S6的磷酸化来激活丝裂原活化蛋白激酶途径和磷酸肌醇3-激酶致癌途径。由于鉴定出了NTRK融合，该患者被纳入了高选择性TRK抑制剂拉罗替尼的I/II期临床试验。患者反应良好，无明显副作用，治疗开始8个月后，增强扫描的肿瘤病灶不再可检测到，符合神经肿瘤学反应评估（RANO）标准中的完全缓解。目前，经过22个月的治疗，患者持续完全缓解。我们的研究结果强调了在BRAF阴性的LGG中筛查其他致癌驱动因素的重要性，因为罕见的融合基因可能成为精准肿瘤治疗的靶点。
