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A Single-Tube Multiplexed Assay for Detecting ALK, ROS1, and RET Fusions in Lung Cancer

 Maruja E. Lira  ;  Yoon-La Choi  ;  Sun Min Lim  ;  Shibing Deng  ;  Donghui Huang  ;  Mark Ozeck  ;  Joungho Han  ;  Ji Yun Jeong  ;  Hyo Sup Shim  ;  Byoung Chul Cho  ;  Jhingook Kim‖  ;  Myung-Ju Ahn  ;  Mao Mao 
 JOURNAL OF MOLECULAR DIAGNOSTICS, Vol.16(2) : 229-243, 2014 
Journal Title
Issue Date
Carcinoma, Non-Small-Cell Lung/diagnosis ; Carcinoma, Non-Small-Cell Lung/genetics ; Female ; Gene Order ; Genetic Testing/methods* ; Humans ; In Situ Hybridization, Fluorescence ; Lung Neoplasms/diagnosis* ; Lung Neoplasms/genetics* ; Male ; Oncogene Proteins, Fusion/genetics* ; Protein-Tyrosine Kinases/genetics* ; Proto-Oncogene Proteins/genetics* ; Proto-Oncogene Proteins c-ret/genetics* ; Receptor Protein-Tyrosine Kinases/genetics* ; Reproducibility of Results ; Reverse Transcriptase Polymerase Chain Reaction ; Sensitivity and Specificity ; Sequence Analysis, DNA ; Transcription, Genetic ; Translocation, Genetic
Approximately 7% of non-small cell lung carcinomas (NSCLCs) harbor oncogenic fusions involving ALK, ROS1, and RET. Although tumors harboring ALK fusions are highly sensitive to crizotinib, emerging preclinical and clinical data demonstrate that patients with ROS1 or RET fusions may also benefit from inhibitors targeting these kinases. Using a transcript-based method, we designed a combination of 3' overexpression and fusion-specific detection strategies to detect ALK, ROS1 and RET fusion transcripts in NSCLC tumors. We validated the assay in 295 NSCLC specimens and showed that the assay is highly sensitive and specific. ALK results were 100% concordant with fluorescence in situ hybridization (FISH) (n = 52) and 97.8% concordant with IHC (n = 179) [sensitivity, 96.8% (95% CI 91.0%-98.9%); specificity, 98.8% (95% CI 93.6%-99.8%)]. For ROS1 and RET, we also observed 100% concordance with FISH (n = 46 and n = 15, respectively). We identified seven ROS1 and 14 RET fusion-positive tumors and confirmed the fusion status by RT-PCR and FISH. One RET fusion involved a novel partner, cutlike homeobox 1 gene (CUX1), yielding an in-frame CUX1-RET fusion. ROS1 and RET fusions were significantly enriched in tumors without KRAS/EGFR/ALK alterations. ALK/ROS1/RET/EGFR/KRAS alterations were mutually exclusive. As a single-tube assay, this test shows promise as a more practical and cost-effective screening modality for detecting rare but targetable fusions in NSCLC.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Shim, Hyo Sup(심효섭) ORCID logo https://orcid.org/0000-0002-5718-3624
Lim, Sun Min(임선민)
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
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