Identification of Novel α and Fusions in NSCLC Plus Additional Novel Fusions in Other Solid Tumors by Whole Transcriptome Sequencing.

INTRODUCTION

A novel fusion has recently been identified in NSCLC. We surveyed a large tumor database comprehensively profiled by whole transcriptome sequencing to investigate the incidence and distribution of fusions among various solid tumors.

METHODS

Tumor samples submitted for clinical molecular profiling at Caris Life Sciences (Phoenix, AZ) that underwent whole transcriptome sequencing (NovaSeq [Illumina, San Diego, CA]) were retrospectively analyzed for fusion events. All fusions with sufficient reads (> three junctional reads spanning ≥ seven nucleotides) were identified for manual review, characterization of fusion class, intact functional domains, EGF-like domain isoforms, breakpoints, frame retention, and co-occurring alterations by next-generation sequencing (NextSeq [Illumina, San Diego, CA], 592 genes).

RESULTS

Seven inframe functional (containing the intact EGF-like domain) fusions were identified, namely, the following: (1) NSCLC (two of 9600, 0.02%: [C11, N2] [F1, N4]); (2) endometrial (two of 3060, 0.065%: [C2, N2], [O1, N2]); (3) ovarian (one of 5030, 0.02%: [S6, N2]); (4) prostate (one of 1600, 0.063%: [P1, N2]); and (5) carcinoma of unknown origin (one of 1400, 0.07%: [C2, N2]). No fusions were identified. Both NSCLC samples contained the reciprocal fusions (, ). Almost all inframe fusions have no (N = 6, 85.7%) or low (N = 1, 14.3%) programmed death-ligand 1 expression. No additional known driver mutations were identified in these seven fusion-positive tumor samples.

CONCLUSIONS

Similar to fusions, fusions are recurrent and rare ligand-fusions in NSCLC and other multiple tumor types, especially gynecologic malignancies.