Metellus Philippe, Camilla Clara, Bialecki Emilie, Beaufils Nathalie, Vellutini Christine, Pellegrino Eric, Tomasini Pascale, Ahluwalia Manmeet S, Mansouri Alireza, Nanni Isabelle, Ouafik L'Houcine
Aix Marseille Univ, Centre national de Recherche Scientifique (CNRS), INP, Inst Neurophysiopathol, Marseille, France.
Ramsay Santé, Hôpital Privé Clairval, Département de Neurochirurgie, Marseille, France.
Front Oncol. 2024 Jul 17;14:1382394. doi: 10.3389/fonc.2024.1382394. eCollection 2024.
Oncogenic fusions of neurotrophic receptor tyrosine kinase , , or genes have been found in different types of solid tumors. The treatment of patients with TRK fusion cancer with a first-generation TRK inhibitor (such as larotrectinib or entrectinib) is associated with high response rates (>75%), regardless of tumor histology and presence of metastases. Due to the efficacy of TRK inhibitor therapy of larotrectinib and entrectinib, it is clinically important to identify patients accurately and efficiently with TRK fusion cancer. In this retrospective study, we provide unique data on the incidence of oncogenic gene fusions in patients with brain metastases (BM) and gliomas.
140 samples fixed and paraffin-embedded tissue (FFPE) of adult patients (59 of gliomas [17 of WHO grade II, 20 of WHO grade III and 22 glioblastomas] and 81 of brain metastasis (BM) of different primary tumors) are analyzed. Identification of gene fusions is performed using next-generation sequencing (NGS) technology using Focus RNA assay kit (Thermo Fisher Scientific).
We identified an () fusion event using targeted next-generation sequencing (NGS) in one of 59 glioma patient with oligodendroglioma-grade II, IDH-mutated and 1p19q co-deleted at incidence of 1.69%. Five additional patients harboring were identified in pancreatic carcinoma brain metastasis (BM), prostatic carcinoma BM, endometrium BM and oligodendroglioma (grade II), IDH-mutated and 1p19q co-deleted. A fusion was identified in one carcinoma breast BM. Aberrant splicing to produce exons 2-7 skipping mRNA, and exon 14 skipping mRNA were identified in glioblastoma and pancreas carcinoma BM, respectively.
This study provides data on the incidence of gene fusions in brain tumors, which could strongly support the relevance of innovative clinical trials with specific targeted therapies (larotrectinib, entrectinib) in this population of patients. rearrangement was detected in breast carcinoma BM with the possibility of using some specific targeted therapies and rearrangements occur in a subset of patients with, prostatic carcinoma BM, endometrium BM, and oligodendroglioma (grade II), IDH-mutated and 1p19q co-deleted, where there are yet no approved ERG-directed therapies.
神经营养性受体酪氨酸激酶、或基因的致癌融合已在不同类型的实体瘤中被发现。使用第一代TRK抑制剂（如拉罗替尼或恩曲替尼）治疗TRK融合癌患者，无论肿瘤组织学类型和有无转移，均有较高的缓解率（>75%）。鉴于拉罗替尼和恩曲替尼的TRK抑制剂治疗效果，准确、高效地识别TRK融合癌患者具有重要的临床意义。在这项回顾性研究中，我们提供了关于脑转移瘤（BM）和胶质瘤患者致癌基因融合发生率的独特数据。
分析了140例成年患者的固定石蜡包埋组织（FFPE）样本（59例胶质瘤[17例WHO二级、20例WHO三级和22例胶质母细胞瘤]以及81例不同原发肿瘤的脑转移瘤（BM））。使用Thermo Fisher Scientific公司的Focus RNA检测试剂盒，通过下一代测序（NGS）技术鉴定基因融合。
在59例少突胶质细胞瘤二级、异柠檬酸脱氢酶（IDH）突变且1p19q共缺失的胶质瘤患者中，通过靶向下一代测序（NGS）在1例患者中鉴定出一个（）融合事件，发生率为1.69%。在胰腺癌脑转移瘤（BM）、前列腺癌BM、子宫内膜癌BM以及少突胶质细胞瘤（二级）、IDH突变且1p19q共缺失的患者中又鉴定出另外5例携带的患者。在1例乳腺癌BM中鉴定出一个融合。在胶质母细胞瘤和胰腺癌BM中分别鉴定出异常剪接产生外显子2 - 7跳跃的mRNA和外显子14跳跃的mRNA。
本研究提供了脑肿瘤中基因融合发生率的数据，这可为针对该患者群体开展特定靶向治疗（拉罗替尼、恩曲替尼）的创新临床试验的相关性提供有力支持。在乳腺癌BM中检测到重排，有可能使用一些特定的靶向治疗，并且在前列腺癌BM、子宫内膜癌BM以及少突胶质细胞瘤（二级）、IDH突变且1p19q共缺失的部分患者中发生重排，而目前尚无批准的针对ERG的治疗方法。
