Novel insights into molecular patterns of ROS1 fusions in a large Chinese NSCLC cohort: a multicenter study
Shengyu Zhou1,2, Fayan Zhang3, Mengxiang Xu4,5
1Clinical Nursing Department, School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, China.
Abstract:
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.
Insights
This study reveals unique breakpoint patterns in ROS1 fusions in Chinese non-small cell lung cancer (NSCLC) patients. Understanding these molecular characteristics aids in targeted therapy for ROS1-rearranged NSCLC.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) rearrangements are key therapeutic targets in non-small cell lung cancer (NSCLC).
- Comprehensive analysis of ROS1 fusion molecular patterns is limited.
- Understanding these patterns is crucial for effective NSCLC treatment strategies.
Purpose of the Study:
- To comprehensively analyze the molecular patterns of ROS1 fusions in Chinese NSCLC patients.
- To identify novel breakpoints and distribution preferences within the ROS1 gene.
- To investigate the association between fusion partners, breakpoints, and NGS methodologies.
Main Methods:
- Analysis of 135 ROS1 fusions from 134 Chinese NSCLC patients using next-generation sequencing (NGS).
- Categorization of fusions into common and uncommon based on incidence.
- Rigorous validation methods to confirm breakpoint consistency between DNA and RNA NGS.
Main Results:
- Identification of a unique distribution preference for common (introns 31-33) and uncommon (introns 34-35) ROS1 fusion breakpoints.
- Discovery of previously unknown breakpoints within intron 28 of ROS1.
- Demonstration of a strong association between fusion partner distribution and ROS1 breakpoint locations.
- Confirmation of inconsistent breakpoints between DNA- and RNA-based NGS due to alternative splicing.
Conclusions:
- The study provides novel insights into the molecular landscape of ROS1 fusions in NSCLC.
- Findings highlight the importance of considering breakpoint distribution and potential NGS inconsistencies for accurate diagnosis.
- This research has direct implications for optimizing diagnostic panel design and guiding therapeutic strategies for ROS1-rearranged NSCLC.
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