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01-12-2022 | NSCLC | Research article

Reliability analysis of exonic-breakpoint fusions identified by DNA sequencing for predicting the efficacy of targeted therapy in non-small cell lung cancer

Authors: Weihua Li, Rui Wan, Lei Guo, Geyun Chang, Dong Jiang, Lin Meng, Jianming Ying

Published in: BMC Medicine | Issue 1/2022

Abstract

Background

Diverse genomic breakpoints of fusions that localize to intronic, exonic, or intergenic regions have been identified by DNA next-generation sequencing (NGS), but the role of exonic breakpoints remains elusive. We investigated whether exonic-breakpoint fusions could predict matched targeted therapy efficacy in non-small cell lung cancer (NSCLC).

Methods

NSCLC samples were analyzed by DNA NGS, RNA NGS, immunohistochemistry (IHC), and fluorescence in situ hybridization.

Results

Using DNA NGS, kinase fusions were identified in 685 of 7148 (9.6%) NSCLCs, with 74 harboring exonic-breakpoint fusions, mostly anaplastic lymphoma kinase (ALK) fusions. RNA NGS and IHC revealed that 11 of 55 (20%) exonic-breakpoint fusions generated no aberrant transcript/protein, possibly due to open reading frame disruption or different gene transcriptional orientations. Four cases of genomic-positive but RNA/protein-negative fusions were treated with matched targeted therapy, but progressive disease developed within 2 months. Nevertheless, 44 of 55 (80%) exonic-breakpoint fusions produced chimeric transcripts/proteins, possibly owing to various alternative splicing patterns, including exon skipping, alternative splice site selection, and intron retention. Most of these genomic- and RNA/protein-positive fusion cases showed a clinical response to matched targeted therapy. Particularly, there were no differences in objective response rate (P = 0.714) or median progression-free survival (P = 0.500) between intronic-breakpoint (n = 56) and exonic-breakpoint ALK fusion subtypes (n = 11) among ALK RNA/protein-validated patients who received first-line crizotinib.

Conclusions

Exonic-breakpoint fusions may generate in-frame fusion transcripts/proteins or not, and thus are unreliable for predicting the efficacy of targeted therapy, which highlights the necessity of implementing RNA or protein assays for functional validation in exonic-breakpoint fusion cases.

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Title: Reliability analysis of exonic-breakpoint fusions identified by DNA sequencing for predicting the efficacy of targeted therapy in non-small cell lung cancer
Authors: Weihua Li
Rui Wan
Lei Guo
Geyun Chang
Dong Jiang
Lin Meng
Jianming Ying
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: NSCLC
Fluorescence in Situ Hybridization
NSCLC
Targeted Therapy
Published in: BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/s12916-022-02362-9

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Reliability analysis of exonic-breakpoint fusions identified by DNA sequencing for predicting the efficacy of targeted therapy in non-small cell lung cancer

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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