RET fusion has emerged as a targetable oncogenic driver in non-small cell lung cancer. The optimal methods to identify actionable RET fusions during clinical practice remain to be evaluated. Herein, we performed a comparative analysis on RET fusions using targeted next-generation sequencing at DNA (DNA-seq) and RNA (RNA-seq) levels.
A total of 53 lung adenocarcinoma patients harboring non-canonical RET fusions identified by DNA-seq were selected to receive RNA-seq of their remaining tumor samples using a 115-cancer gene panel (OncoRNA). Of them, 43 passed quality control of RNA-seq. The breakpoints and partners of RET-fusion identified by DNA- and RNA-Seq were described and compared.
Of the 43 patients, DNA-seq identified 25 patients with concurrent 5’ RET fusions and 3’ canonical RET fusions (KIF5B-RET (K15:R12) or CCDC6-RET (C1:R12), subgroup A), 2 patients with 5’ RET fusions alone (subgroup B), 8 patients with frameshift or out-of-frame fusions (subgroup C) and 8 patients with 3’ non-canonical RET fusions alone (subgroup D). In total, 40 of 43 patients (93%) were positive for RET-fusions at RNA level. In subgroup A, RNA-seq detected all canonical RET-fusions with identical breakpoints to DNA-seq, while no transcripts of the 5’ RET fusions were detected. Patients in subgroups B and C did not have in-frame actionable fusions detected by DNA-seq. However, in subgroup B, RNA-seq identified 1 KIF5B-RET transcript with rare breakpoint (K24:R10). In subgroup C, only 1 patient was negative while 7 patients were positive at RNA level including 6 with canonical RET fusions of which the RET breakpoints were identical to DNA-seq. The discordance might be explained by complex DNA structural rearrangements and RNA splicing. In subgroup D, RNA-seq identified 7 of 8 patients with RET fusions concordant with DNA-seq, and 1 patient was negative. Most RET fusions in this subgroup involved rare partners including KIAA1468, LMNA, TRIM33, EDC4, ANKRD26, and AKAP13.
DNA-seq and RNA-seq showed high consistency in detecting RET fusions. RNA-seq could be valuable in determining the actionability of 5’ or frameshift/out-of-frame DNA fusions.
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All authors have declared no conflicts of interest.