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Response to crizotinib in a non-small-cell lung cancer patient harboring an EML4-ALK fusion with an atypical LTBP1 insertion

Authors Aguado C, Gil MDLL, Yeste Z, Giménez-Capitán A, Teixidó C, Karachaliou N, Viteri S, Rosell R, Molina-Vila MA

Received 4 August 2017

Accepted for publication 18 November 2017

Published 1 March 2018 Volume 2018:11 Pages 1117—1120

DOI https://doi.org/10.2147/OTT.S148363

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Prof. Dr. Jianmin Xu


Cristina Aguado,1,* Maria-de-los-Llanos Gil,2,* Zaira Yeste,1 Ana Giménez-Capitán,1 Cristina Teixidó,1 Niki Karachaliou,2 Santiago Viteri,2 Rafael Rosell,1,2 Miguel A Molina-Vila1

1Laboratory of Oncology, Pangaea Oncology, 2Dr Rosell Oncology Institute, Quirón Dexeus University Hospital, Barcelona, Spain

*These authors contributed equally to this work

Abstract: Fusion of the anaplastic lymphoma receptor tyrosine kinase gene (ALK) with the echinoderm microtubule-associated protein 4 gene (EML4) is the second most common actionable alteration in non-small-cell lung cancer, with a frequency of 5%. Here, we present a case of an EML4-ALK-positive patient with an atypical in-frame insertion from the LTBP1 gene in the canonical junction of variant 1. The patient was a 39-year-old never-smoker female diagnosed with Stage IV lung adenocarcinoma. A core biopsy was negative for EGFR and KRAS mutations but positive for ALK immunohistochemistry and fluorescence in situ hybridization. When submitted to nCounter, the sample showed a 3'/5' imbalance indicative of an ALK rearrangement, but failed to give a positive signal for any of the variants tested. Finally, a band with a molecular weight higher than expected appeared after reverse transcriptase-polymerase chain reaction analysis. When Sanger sequencing was performed, the band revealed an atypical EML4-ALK fusion gene with an in-frame 129 bp insertion. A 115 bp segment of the insertion corresponded to an intronic region of LTBP1, a gene located in the short arm of chromosome 2, between ALK and EML4. The patient received crizotinib and showed a good therapeutic response that is still ongoing after 12 months. Our result suggests that short in-frame insertions of other genes in the EML4-ALK junction do not affect the sensitivity of the EML4-ALK fusion protein to crizotinib.

Keywords: lung cancer, NSCLC, EML4-ALK, LTBP1, crizotinib, targeted therapy

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