Abstract 1148P
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.