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

Abstract

Introduction: A novel CD74-NRG2a 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) NRG2a fusions were identified, namely, the following: (1) NSCLC (two of 9600, 0.

NRG1 and NRG2 fusion positive solid tumor malignancies: a paradigm of ligand-fusion oncogenesis

“…A total of seven NRG1 fusions were identified in the same study, indicating NRG2 fusions are even rarer than NRG1 fusions [10,55]. All known NRG2 fusions identified to date contain the EGFR-like α-isoform domain, a theoretically lower binding affinity ligand than the β-isoform of NRG2 [9,10].…”

“…In contrast, in the three cases of CD74-NRG1, all four members of the HER family (EGFR, HER2, HER3, HER4) were phosphorylated, indicating further that NRG1/HER3 is more active than the NRG2/HER4 signaling pathway. Subsequently, a pan-tumor survey was performed in approximately 54 000 solid tumors and identified seven NRG2 fusions among NSCLC (2/9600, 0.021%), endometrial (2/2600, 0.065%), ovarian (1/5030, 0.020%), and prostate cancer (1/1600, 0.065%) and adenocarcinoma of unknown primary by WTS [10] (Figure I). The same F11R-NRG2 fusion identified in NSCLC was also found at 0.5% (1/200) in cases of invasive mucinous adenocarcinoma (IMA) [55].…”

“…Subsequent knockout experiments indicated that NRG2 may be involved in regional development in the central nervous system and that the loss of NRG2 may lead animals to display behavioral characteristics of human psychiatric disease [42]. Thus, normal function of NRG2 is subtle and remains to be fully elucidated and the biological significance of NRG2 fusions in solid tumors is to be determined [9,10].…”

“…The overall incidence of NRG1 and NRG2 fusions is very rare [5,9,10,[43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58]. In many tumor types, only limited numbers (or even just one) of NRG1 or NRG2 fusion variant have been identified.…”

“…tumors. Indirectly supporting this conclusion is the recent discovery of an even rarer neuregulin-2 fusion (NRG2+) [9,10], where the normal physiological function of NRG2 remains to be fully elucidated.…”