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ALK fusion variants detection by targeted RNA-next generation sequencing and clinical responses to crizotinib in ALK-positive non-small cell lung cancer.
Lung Cancer 2018; 116:15-24LC

Abstract

OBJECTIVES

The aim of the present study was firstly to assess in a clinical setting the yields of an amplicon-based parallel RNA sequencing (RNA-seq) assay for ALK fusion transcript variants detection in comparison with immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH) in a selected population of ALK-positive and ALK-negative non-small cell lung cancer (NSCLC) cases, and secondly to evaluate the impact of the ALK variant on crizotinib efficacy.

MATERIALS AND METHODS

The cohort used for the assessment of the RNA-seq assay comprised 53 samples initially diagnosed as being ALK-positive based on the results obtained by IHC and/or FISH, and 23 ALK-negative samples. A distinction was made between 'truly' IHC/FISH positive or 'truly' IHC/FISH negative samples, and those for which the IHC and/or FISH were equivocal (IHC) or borderline-positive (FISH).

RESULTS

On the overall population, RNA-seq sensitivity (Se) and specificity (Spe) were of 80% and 100%, respectively when IHC and FISH were combined. For the 31 'truly positive' samples, Se and Spe of 100% were reached. An ALK status could be assigned by RNA-seq in 10/10 of the equivocal and/or borderline-positive IHC/FISH cases, 2/7 IHC/FISH discordant cases. When crizotinib efficacy was evaluated according to the type of ALK variant, better clinical outcomes were observed in crizotinib-treated patients with EML4-ALK v1/v2/others variants compared to v3a/b variants.

CONCLUSION

RNA-seq detects ALK rearrangements with a high sensitivity and specificity using only 10 ng of RNA. It appears to be a promising rescue technique for non-clear-cut IHC/FISH cases and also offers a unique opportunity to identify ALK fusion variants and evaluate their predictive value for ALK inhibitors efficacy.

Authors+Show Affiliations

Département d'Anatomie et Cytologie Pathologiques, Pôle de Biologie et Pathologie, CHU Grenoble Alpes, Grenoble, France; Plateforme de Génétique Moléculaire des Cancers, Pôle de Biologie et Pathologie, CHU Grenoble Alpes, Grenoble, France; UGA/INSERM U1209/CNRS 5309-Institute for Advanced Biosciences-Université Grenoble Alpes, Grenoble, France; Université Grenoble Alpes, Grenoble, France. Electronic address: AMcleer@chu-grenoble.fr.Clinique de Pneumologie, Unité d'Oncologie Thoracique, Pôle Thorax et Vaisseaux, CHU Grenoble Alpes, Grenoble, France; UGA/INSERM U1209/CNRS 5309-Institute for Advanced Biosciences-Université Grenoble Alpes, Grenoble, France.Clinique de Pneumologie, Unité d'Oncologie Thoracique, Pôle Thorax et Vaisseaux, CHU Grenoble Alpes, Grenoble, France; UGA/INSERM U1209/CNRS 5309-Institute for Advanced Biosciences-Université Grenoble Alpes, Grenoble, France.Plateforme de Génétique Moléculaire des Cancers, Pôle de Biologie et Pathologie, CHU Grenoble Alpes, Grenoble, France.Département d'Anatomie et Cytologie Pathologiques, Pôle de Biologie et Pathologie, CHU Grenoble Alpes, Grenoble, France; Plateforme de Génétique Moléculaire des Cancers, Pôle de Biologie et Pathologie, CHU Grenoble Alpes, Grenoble, France; TheRex TIMC-IMAG CNRS UMR 5525, Grenoble, France; Université Grenoble Alpes, Grenoble, France.Clinique de Pneumologie, Unité d'Oncologie Thoracique, Pôle Thorax et Vaisseaux, CHU Grenoble Alpes, Grenoble, France; UGA/INSERM U1209/CNRS 5309-Institute for Advanced Biosciences-Université Grenoble Alpes, Grenoble, France.Plateforme de Génétique Moléculaire des Cancers, Pôle de Biologie et Pathologie, CHU Grenoble Alpes, Grenoble, France.Plateforme de Biologie Moléculaire, Pôle de Biologie et Pathologie, CHU Grenoble Alpes, Grenoble, France; Université Grenoble Alpes, Grenoble, France.Plateforme de Biologie Moléculaire, Pôle de Biologie et Pathologie, CHU Grenoble Alpes, Grenoble, France.Plateforme de Génétique Moléculaire des Cancers, Pôle de Biologie et Pathologie, CHU Grenoble Alpes, Grenoble, France; UGA/INSERM U1209/CNRS 5309-Institute for Advanced Biosciences-Université Grenoble Alpes, Grenoble, France.Clinique de Pneumologie, Unité d'Oncologie Thoracique, Pôle Thorax et Vaisseaux, CHU Grenoble Alpes, Grenoble, France; UGA/INSERM U1209/CNRS 5309-Institute for Advanced Biosciences-Université Grenoble Alpes, Grenoble, France.Clinique de Pneumologie, Unité d'Oncologie Thoracique, Pôle Thorax et Vaisseaux, CHU Grenoble Alpes, Grenoble, France; UGA/INSERM U1209/CNRS 5309-Institute for Advanced Biosciences-Université Grenoble Alpes, Grenoble, France; Université Grenoble Alpes, Grenoble, France.Clinique Universitaire de Radiologie et Imagerie, CHU Grenoble Alpes, Grenoble, France; UGA/INSERM U1209/CNRS 5309-Institute for Advanced Biosciences-Université Grenoble Alpes, Grenoble, France; Université Grenoble Alpes, Grenoble, France.Plateforme de Génétique Moléculaire des Cancers, Pôle de Biologie et Pathologie, CHU Grenoble Alpes, Grenoble, France; UGA/INSERM U1209/CNRS 5309-Institute for Advanced Biosciences-Université Grenoble Alpes, Grenoble, France; Université Grenoble Alpes, Grenoble, France.UGA/INSERM U1209/CNRS 5309-Institute for Advanced Biosciences-Université Grenoble Alpes, Grenoble, France; Université Grenoble Alpes, Grenoble, France.Clinique de Pneumologie, Unité d'Oncologie Thoracique, Pôle Thorax et Vaisseaux, CHU Grenoble Alpes, Grenoble, France; UGA/INSERM U1209/CNRS 5309-Institute for Advanced Biosciences-Université Grenoble Alpes, Grenoble, France; Université Grenoble Alpes, Grenoble, France.UGA/INSERM U1209/CNRS 5309-Institute for Advanced Biosciences-Université Grenoble Alpes, Grenoble, France; Université Grenoble Alpes, Grenoble, France; Département de biopathologie-MESOPATH, Centre de Lutte Contre le Cancer Léon Bérard, Lyon, France.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29413046

Citation

McLeer-Florin, Anne, et al. "ALK Fusion Variants Detection By Targeted RNA-next Generation Sequencing and Clinical Responses to Crizotinib in ALK-positive Non-small Cell Lung Cancer." Lung Cancer (Amsterdam, Netherlands), vol. 116, 2018, pp. 15-24.
McLeer-Florin A, Duruisseaux M, Pinsolle J, et al. ALK fusion variants detection by targeted RNA-next generation sequencing and clinical responses to crizotinib in ALK-positive non-small cell lung cancer. Lung Cancer. 2018;116:15-24.
McLeer-Florin, A., Duruisseaux, M., Pinsolle, J., Dubourd, S., Mondet, J., Phillips Houlbracq, M., ... Lantuejoul, S. (2018). ALK fusion variants detection by targeted RNA-next generation sequencing and clinical responses to crizotinib in ALK-positive non-small cell lung cancer. Lung Cancer (Amsterdam, Netherlands), 116, pp. 15-24. doi:10.1016/j.lungcan.2017.12.004.
McLeer-Florin A, et al. ALK Fusion Variants Detection By Targeted RNA-next Generation Sequencing and Clinical Responses to Crizotinib in ALK-positive Non-small Cell Lung Cancer. Lung Cancer. 2018;116:15-24. PubMed PMID: 29413046.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ALK fusion variants detection by targeted RNA-next generation sequencing and clinical responses to crizotinib in ALK-positive non-small cell lung cancer. AU - McLeer-Florin,Anne, AU - Duruisseaux,Michael, AU - Pinsolle,Julian, AU - Dubourd,Sylvian, AU - Mondet,Julie, AU - Phillips Houlbracq,Mathilde, AU - Magnat,Nelly, AU - Fauré,Julien, AU - Chatagnon,Amandine, AU - de Fraipont,Florence, AU - Giaj Levra,Matteo, AU - Toffart,Anne-Claire, AU - Ferretti,Gilbert, AU - Hainaut,Pierre, AU - Brambilla,Elisabeth, AU - Moro-Sibilot,Denis, AU - Lantuejoul,Sylvie, Y1 - 2017/12/08/ PY - 2017/09/28/received PY - 2017/12/05/revised PY - 2017/12/06/accepted PY - 2018/2/8/entrez PY - 2018/2/8/pubmed PY - 2019/2/5/medline KW - ALK KW - Borderline-positive FISH KW - Crizotinib KW - FISH KW - IHC KW - Lung KW - NGS KW - RNA-seq SP - 15 EP - 24 JF - Lung cancer (Amsterdam, Netherlands) JO - Lung Cancer VL - 116 N2 - OBJECTIVES: The aim of the present study was firstly to assess in a clinical setting the yields of an amplicon-based parallel RNA sequencing (RNA-seq) assay for ALK fusion transcript variants detection in comparison with immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH) in a selected population of ALK-positive and ALK-negative non-small cell lung cancer (NSCLC) cases, and secondly to evaluate the impact of the ALK variant on crizotinib efficacy. MATERIALS AND METHODS: The cohort used for the assessment of the RNA-seq assay comprised 53 samples initially diagnosed as being ALK-positive based on the results obtained by IHC and/or FISH, and 23 ALK-negative samples. A distinction was made between 'truly' IHC/FISH positive or 'truly' IHC/FISH negative samples, and those for which the IHC and/or FISH were equivocal (IHC) or borderline-positive (FISH). RESULTS: On the overall population, RNA-seq sensitivity (Se) and specificity (Spe) were of 80% and 100%, respectively when IHC and FISH were combined. For the 31 'truly positive' samples, Se and Spe of 100% were reached. An ALK status could be assigned by RNA-seq in 10/10 of the equivocal and/or borderline-positive IHC/FISH cases, 2/7 IHC/FISH discordant cases. When crizotinib efficacy was evaluated according to the type of ALK variant, better clinical outcomes were observed in crizotinib-treated patients with EML4-ALK v1/v2/others variants compared to v3a/b variants. CONCLUSION: RNA-seq detects ALK rearrangements with a high sensitivity and specificity using only 10 ng of RNA. It appears to be a promising rescue technique for non-clear-cut IHC/FISH cases and also offers a unique opportunity to identify ALK fusion variants and evaluate their predictive value for ALK inhibitors efficacy. SN - 1872-8332 UR - https://www.unboundmedicine.com/medline/citation/29413046/ALK_fusion_variants_detection_by_targeted_RNA_next_generation_sequencing_and_clinical_responses_to_crizotinib_in_ALK_positive_non_small_cell_lung_cancer_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0169-5002(17)30601-3 DB - PRIME DP - Unbound Medicine ER -