Identification of Novel CDH1-NRG2 α and F11R-NRG2α Fusions in NSCLC Plus Additional Novel NRG2α Fusions in Other Solid Tumors by Whole Transcriptome Sequencing

Abstract

Introduction: A novel CD74-NRG2α 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 NRG2 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 NRG2 fusion events. All NRG2 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) NRG2α fusions were identified, namely, the following: (1) NSCLC (two of 9600, 0.02%: CDH1-NRG2α [C11, N2], F11R-NRG2α [F1, N4]); (2) endometrial (two of 3060, 0.065%: CPM-NRG2α [C2, N2], OPA3-NRG2α [O1, N2]); (3) ovarian (one of 5030, 0.02%: SPON1-NRG2α [S6, N2]); (4) prostate (one of 1600, 0.063%: PLPP1-NRG2α [P1, N2]); and (5) carcinoma of unknown origin (one of 1400, 0.07%: CYSTM1-NRG2α [C2, N2]). No NRG2β fusions were identified. Both NSCLC samples contained the reciprocal NRG2 fusions (NRG2-CDH1, NRG2-F11R). Almost all inframe NRG2α 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 NRG2α fusion-positive tumor samples.

Conclusions: Similar to NRG1 fusions, NRG2α fusions are recurrent and rare ligand-fusions in NSCLC and other multiple tumor types, especially gynecologic malignancies.

Keywords: CDH1-NRG2α; F11R-NRG2α; NRG2 fusion; Whole transcriptome sequencing; ligand-fusion- positive malignancies.

Figure 1

(A) A schematic of the seven inframe NRG2α fusions. (B) A schematic of the generation of the full EGF-like domain from the differential splicing of the EGF-like core domain and the α or β isoform. The alignment of amino acid sequences of EGF-like domain between NRG2α and NRG2β with reference to the EGF domain of EGFR are shown with the aqua color highlighted region representing the α-isoform and the green color highlighted representing the β-isoform. Modified from Jones et al. Ig-like, immunoglobulin-like; NFR2, neuregulin-2.