Zhou Shengyu, Zhang Fayan, Xu Mengxiang, Zhang Lei, Liu Zhengchuang, Yang Qiong, Wang Chunyang, Wang Baoming, Ma Tonghui, Feng Jiao
Clinical Nursing Department, School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, China.
Department of Respiratory and Critical Care Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Mol Oncol. 2023 Oct;17(10):2200-2212. doi: 10.1002/1878-0261.13509. Epub 2023 Aug 28.
ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) rearrangements are a crucial therapeutic target in non-small cell lung cancer (NSCLC). However, there is limited comprehensive analysis of the molecular patterns of ROS1 fusions. This study aimed to address this gap by analysing 135 ROS1 fusions from 134 Chinese NSCLC patients using next-generation sequencing (NGS). The fusions were categorized into common and uncommon based on their incidence. Our study revealed, for the first time, a unique distribution preference of breakpoints within ROS1, with common fusions occurring in introns 31-33 and uncommon fusions occurring in introns 34 and 35. Additionally, we identified previously unknown breakpoints within intron 28 of ROS1. Furthermore, we identified a close association between the distribution patterns of fusion partners and breakpoints on ROS1, providing important insights into the molecular landscape of ROS1 fusions. We also confirmed the presence of inconsistent breakpoints in ROS1 fusions between DNA-based NGS and RNA-based NGS through rigorous validation methods. These inconsistencies were attributed to alternative splicing resulting in out-of-frame or exonic ROS1 fusions. These findings significantly contribute to our understanding of the molecular characteristics of ROS1 fusions, which have implications for panel design and the treatment of NSCLC patients with ROS1 rearrangements.
ROS原癌基因1，受体酪氨酸激酶（ROS1）重排是非小细胞肺癌（NSCLC）中一个关键的治疗靶点。然而，对ROS1融合分子模式的全面分析有限。本研究旨在通过使用二代测序（NGS）分析134例中国NSCLC患者的135个ROS1融合来填补这一空白。根据其发生率将融合分为常见和不常见两类。我们的研究首次揭示了ROS1内断点的独特分布偏好，常见融合发生在第31 - 33内含子，不常见融合发生在第34和35内含子。此外，我们在ROS1的第28内含子内鉴定出了先前未知的断点。此外，我们确定了融合伴侣的分布模式与ROS1上断点之间的密切关联，为ROS1融合的分子格局提供了重要见解。我们还通过严格的验证方法证实了基于DNA的NGS和基于RNA的NGS之间ROS1融合存在不一致的断点。这些不一致归因于可变剪接导致的移码或外显子ROS1融合。这些发现显著有助于我们理解ROS1融合的分子特征，这对检测板设计以及ROS1重排的NSCLC患者的治疗具有重要意义。
