PO.ET06.05 · 实验与分子治疗
在中国NSCLC中，基于扩增子的DNA和RNA NGS联合检测相比杂交捕获DNA-NGS可增强ROS1融合检出并提高伴侣多样性
Amplicon-based DNA and RNA NGS co-detection enhances ROS1 fusion detection and partner diversity compared with hybrid-capture DNA-NGS in Chinese NSCLC
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摘要 Abstract
中文摘要
背景：ROS1重排是非小细胞肺癌（NSCLC）中重要的可干预驱动因素，但传统的基于DNA的检测方法对检测这些融合的灵敏度有限。已证明RNA-NGS在融合检测方面优于DNA-NGS；然而，在大规模真实世界NSCLC人群中，基于扩增子的DNA+RNA NGS联合检测与杂交捕获DNA-NGS在识别ROS1融合方面的相对性能仍未得到充分表征。
方法：我们回顾性分析了采用两种二代测序策略检测NSCLC样本中的ROS1融合：一种35基因、基于扩增子的DNA+RNA NGS联合检测法（n = 11,242）和一种杂交捕获DNA-NGS法（n = 2,504）。对两种方法均识别ROS1融合阳性病例，并对所有确认的重排标注融合伴侣。比较检出率和伴侣多样性，以评估两个平台之间分析性能的差异。
结果：基于扩增子的DNA+RNA NGS联合检测显示出比杂交捕获DNA-NGS更高的ROS1融合检出率（1.82%，205/11,242 vs 1.56%，39/2,504）。基于扩增子的DNA+RNA NGS联合检测识别出多种经典5′-3′ ROS1融合伴侣，其中最常见的是CD74-ROS1（46.34%）、EZR-ROS1（22.93%）和SDC4-ROS1（16.10%），其次是较不常见的伴侣，如TPM3-ROS1（10/205，4.88%）、SLC34A2-ROS1（7/205，3.41%）、CCDC6-ROS1（5/205，2.44%）、GOPC-ROS1（2/205，0.98%）、TPR-ROS1（2/205，0.98%），以及若干罕见事件，包括EML4-ROS1（1/205，0.49%）、LRIG3-ROS1（1/205，0.49%）、PPFIBPI-ROS1（1/205，0.49%）和ZCCHC8-ROS1（1/205，0.49%）。相比之下，杂交捕获DNA-NGS检测到的伴侣谱更窄，以CD74-ROS1（58.97%）、SDC4-ROS1（20.51%）和EZR-ROS1（12.82%）为主，仅有个别的GOPC-ROS1、TPM3-ROS1和单个ROS1-SLC34A2事件。两种方法检测到的所有重排均为经典5′-3′融合。
结论：在这个大规模真实世界队列中，基于扩增子的DNA+RNA NGS联合检测优于杂交捕获DNA-NGS，其ROS1融合检出率更高，并揭示了更为多样的ROS1融合伴侣谱。这些发现强调了将基于RNA的分析整合到常规NGS工作流程中以提高可干预基因融合检测准确性的重要性，并支持为NSCLC患者制定更精准的治疗决策。
查看英文原文 English abstract
Background: ROS1 rearrangements are important actionable drivers in non-small cell lung cancer (NSCLC), yet traditional DNA-based assays show limited sensitivity for detecting these fusions. RNA-NGS has been demonstrated to outperform DNA-NGS in fusion detection; however, the relative performance of amplicon-based DNA+RNA NGS co-detection versus hybrid-capture DNA-NGS for identifying ROS1 fusions in large real-world NSCLC populations remains insufficiently characterized.
Methods: We retrospectively analyzed ROS1 fusion detection in NSCLC samples using two next-generation sequencing strategies: a 35-gene amplicon-based DNA+RNA NGS co-detection assay (n = 11,242) and a hybrid-capture DNA-NGS assay (n = 2,504). For both approaches, ROS1 fusion-positive cases were identified, and all confirmed rearrangements were annotated for fusion partners. Detection rates and partner diversity were compared to evaluate differences in analytical performance between the two platforms.
Results: Amplicon-based DNA+RNA NGS co-detection demonstrated a higher ROS1 fusion detection rate (1.82%, 205/11,242) than hybrid-capture DNA-NGS (1.56%, 39/2,504). Amplicon-based DNA+RNA NGS co-detection identified a wide variety of classical 5′-3′ ROS1 fusion partners, with CD74-ROS1 (46.34%), EZR-ROS1 (22.93%), and SDC4-ROS1 (16.10%) being the most prevalent, followed by less frequent partners such as TPM3-ROS1(10/205, 4.88%), SLC34A2-ROS1(7/205,3.41%), CCDC6-ROS1(5/205,2.44%), GOPC-ROS1(2/205,0.98%), TPR-ROS1(2/205,0.98%), and several rare events including EML4-ROS1(1/205,0.49%), LRIG3-ROS1(1/205,0.49%), PPFIBPI-ROS1(1/205,0.49%), and ZCCHC8-ROS1(1/205,0.49%). In contrast, hybrid-capture DNA-NGS detected a narrower spectrum of partners, dominated by CD74-ROS1 (58.97%), SDC4-ROS1 (20.51%), and EZR-ROS1 (12.82%), with only isolated occurrences of GOPC-ROS1, TPM3-ROS1, and a single ROS1-SLC34A2 event. All rearrangements detected by either method were classical 5′-3′ fusions.
Conclusion: In this large real-world cohort, amplicon-based DNA+RNA NGS co-detection outperformed hybrid-capture DNA-NGS by yielding a higher ROS1 fusion detection rate and uncovering a more diverse spectrum of ROS1 fusion partners. These findings highlight the importance of integrating RNA-based analysis into routine NGS workflows to enhance the detection accuracy of actionable gene fusions and support more precise therapeutic decision-making for patients with NSCLC.
利益披露 Disclosure
Y. Zebo, None.