Department of Pathology, Peking Union Medical College Hospital, and Molecular Pathology Research Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Pathology, Peking Union Medical College Hospital, and Molecular Pathology Research Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
J Mol Diagn. 2023 Aug;25(8):569-582. doi: 10.1016/j.jmoldx.2023.04.007. Epub 2023 May 25.
Rare NTRK-driven malignant neoplasms can be effectively inhibited by anti-TRK agents. The discovery of NTRK1/2/3-rich tumors in papillary thyroid cancer (PTC) patients is a precondition for the rapid identification of NTRK fusion tumors. Knowledge of NTRK gene activation is critical to accurately detect NTRK status. A total of 229 BRAF V600E-negative samples from PTC patients were analyzed in this study. Break-apart fluorescence in situ hybridization (FISH) was performed to detect RET fusion. NTRK status was analyzed using FISH, DNA- and RNA-based next-generation sequencing, and quantitative reverse transcription PCR. In 128 BRAF and RET double-negative cases, 56 (43.8%, 56/128) NTRK rearrangement tumors were found, including 1 NTRK2, 16 NTRK1, and 39 NTRK3 fusions. Two novel NTRK fusions, EZR::NTRK1 and EML4::NTRK2, were found in the NTRK rearrangement tumors. Dominant break-apart and extra 3' signal patterns accounted for 89.3% (50/56) and 5.4% (3/56) of all NTRK-positive cases, respectively, as determined by FISH. In this study's cohort, there were 2.3% (3/128) FISH false-negative and 3.1% (4/128) FISH false-positive cases identified. NTRK fusions are highly recurrent in BRAF and RET double-negative PTCs. FISH- or RNA-based next-generation sequencing is a reliable detection approach. NTRK rearrangement can be precisely, rapidly, and economically detected based on the developed optimal algorithm.
罕见的 NTRK 驱动的恶性肿瘤可以被抗 TRK 药物有效地抑制。在甲状腺乳头状癌（PTC）患者中发现富含 NTRK1/2/3 的肿瘤是快速识别 NTRK 融合肿瘤的前提。了解 NTRK 基因的激活对于准确检测 NTRK 状态至关重要。本研究分析了 229 例 BRAF V600E 阴性的 PTC 患者样本。采用分离荧光原位杂交（FISH）检测 RET 融合。使用 FISH、基于 DNA 和 RNA 的下一代测序以及实时定量逆转录 PCR 分析 NTRK 状态。在 128 例 BRAF 和 RET 双阴性病例中，发现 56 例（43.8%，56/128）NTRK 重排肿瘤，包括 1 例 NTRK2、16 例 NTRK1 和 39 例 NTRK3 融合。在 NTRK 重排肿瘤中发现了 2 种新的 NTRK 融合，EZR::NTRK1 和 EML4::NTRK2。通过 FISH 确定，所有 NTRK 阳性病例中，占主导地位的分离和额外的 3'信号模式分别占 89.3%（50/56）和 5.4%（3/56）。在本研究队列中，FISH 假阴性率为 2.3%（3/128），FISH 假阳性率为 3.1%（4/128）。BRAF 和 RET 双阴性 PTC 中 NTRK 融合高度复发。FISH 或基于 RNA 的下一代测序是一种可靠的检测方法。基于开发的最佳算法，可以精确、快速和经济地检测 NTRK 重排。
