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

• Main Authors: Sai-Hong Ignatius Ou, MD, PhD, Joanne Xiu, PhD, Misako Nagasaka, MD, Bing Xia, MD, Shannon S. Zhang, MD, Qing Zhang, PhD, Jeffrey J. Swensen, PhD, David Spetzler, MS, PhD, MBA, Wolfgang Michael Korn, MD, Viola W. Zhu, MD, PhD, Stephen V. Liu, MD
• Format: Article
• Language: English
• Published: Elsevier 2021-02-01
• Series: JTO Clinical and Research Reports
• Subjects: NRG2 fusion; CDH1-NRG2α; F11R-NRG2α; Whole transcriptome sequencing; ligand-fusion- positive malignancies
• Online Access: http://www.sciencedirect.com/science/article/pii/S2666364320301831

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.