Abstract
BackgroundComplex kinase rearrangement, a mutational process involving one or two chromosomes with clustered rearrangement breakpoints, interferes with the accurate detection of kinase fusions by DNA-based next-generation sequencing (NGS). We investigated the characteristics of complex ALK rearrangements in non-small cell lung cancers using multiple molecular tests.MethodsSamples of non-small cell lung cancer patients were analyzed by targeted-capture DNA-based NGS with probes tilling the selected intronic regions of fusion partner genes, RNA-based NGS, RT-PCR, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH).ResultsIn a large cohort of 6576 non-small cell lung cancer patients, 343 (5.2%) cases harboring ALK rearrangements were identified. Fourteen cases with complex ALK rearrangements were identified by DNA-based NGS and classified into three types by integrating various genomic features, including intergenic (n = 3), intragenic (n = 5) and “bridge joint” rearrangements (n = 6). All thirteen cases with sufficient samples actually expressed canonical EML4-ALK fusion transcripts confirmed by RNA-based NGS. Besides, positive ALK IHC was detected in 13 of 13 cases, and 9 of 11 cases were positive in FISH testing. Patients with complex ALK rearrangements who received ALK inhibitors treatment (n = 6), showed no difference in progression-free survival (PFS) compared with patients with canonical ALK fusions n = 36, P = 0.9291).ConclusionsThis study firstly reveals the molecular characteristics and clinical outcomes of complex ALK rearrangements in NSCLC, sensitive to ALK inhibitors treatment, and highlights the importance of utilizing probes tilling the selected intronic regions of fusion partner genes in DNA-based NGS for accurate fusion detection. RNA and protein level assay may be critical in validating the function of complex ALK rearrangements in clinical practice for optimal treatment decision.
Highlights
Complex kinase rearrangement, a mutational process involving one or two chromosomes with clustered rearrangement breakpoints, interferes with the accurate detection of kinase fusions by DNA-based nextgeneration sequencing (NGS)
Characteristics of patients and anaplastic lymphoma kinase (ALK) rearrangements All of 6576 samples from non-small cell lung cancer (NSCLC) patients were profiled with DNA-based NGS between January 2018 and July 2020
Canonical echinoderm microtubule-associated protein like-4 (EML4)-ALK fusions occurred most frequently accounting for 78.4% (269/343)
Summary
A mutational process involving one or two chromosomes with clustered rearrangement breakpoints, interferes with the accurate detection of kinase fusions by DNA-based nextgeneration sequencing (NGS). We investigated the characteristics of complex ALK rearrangements in non-small cell lung cancers using multiple molecular tests. Rearrangements of the anaplastic lymphoma kinase (ALK) gene have been identified in approximately 3–7% of non-small cell lung cancer (NSCLC) patients, with echinoderm microtubule-associated protein like-4 (EML4) representing the most common fusion partner [1, 2]. ALK-rearranged NSCLC define a distinct molecular subset with high sensitivity to ALK tyrosine kinase inhibitors (TKIs). Crizotinib, a well-tolerated first generation ALK inhibitor [3, 4], has been approved by Food and Drug Administration in US for the treatment of ALK-rearranged NSCLC in 2011. The identification of ALK rearrangements and the approval of a number of ALK TKIs have revolutionized the treatment of patients harboring ALK fusions.
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