Identification of tumors with NRG1 rearrangement, including a novel putative pathogenic UNC5D‐NRG1 gene fusion in prostate cancer by data‐drilling a de‐identified tumor database

Abstract

The fusion genes containing neuregulin‐1 (NRG1) are newly described potentially actionable oncogenic drivers. Initial clinical trials have shown a positive response to targeted treatment in some cases of NRG1 rearranged lung adenocarcinoma, cholangiocarcinoma, and pancreatic carcinoma. The cost‐effective large scale identification of NRG1 rearranged tumors is an open question. We have tested a data‐drilling approach by performing a retrospective assessment of a de‐identified molecular profiling database of 3263 tumors submitted for fusion testing. Gene fusion detection was performed by RNA‐based targeted next‐generation sequencing using the Archer Fusion Plex kits for Illumina (ArcherDX Inc., Boulder, CO). Novel fusion transcripts were confirmed by a custom‐designed RT‐PCR. Also, the aberrant expression of CK20 was studied immunohistochemically. The frequency of NRG1 rearranged tumors was 0.2% (7/3263). The most common histologic type was lung adenocarcinoma (n = 5). Also, renal carcinoma (n = 1) and prostatic adenocarcinoma (n = 1) were found. Identified fusion partners were of a wide range (CD74, SDC4, TNC, VAMP2, UNC5D), with CD74, SDC4 being found twice. The UNC5D is a novel fusion partner identified in prostate adenocarcinoma. There was no co‐occurrence with the other tested fusions nor KRAS, BRAF, and the other gene mutations specified in the applied gene panels. Immunohistochemically, the focal expression of CK20 was present in 2 lung adenocarcinomas. We believe it should be considered as an incidental finding. In conclusion, the overall frequency of tumors with NRG1 fusion was 0.2%. All tumors were carcinomas. We confirm (invasive mucinous) lung adenocarcinoma as being the most frequent tumor presenting NRG1 fusion. Herein novel putative pathogenic gene fusion UNC5D‐NRG1 is described. The potential role of immunohistochemistry in tumor identification should be further addressed.

Novel TNC-PDGFD fusion in fibrosarcomatous dermatofibrosarcoma protuberans: a case report

“…TNC has oncogenic properties through promotion of cell proliferation, migration and angiogenesis and its over-expression has been linked to a variety of malignancies [ 18 ]. Recently, fusions involving TNC have rarely been documented to occur in other neoplasms, including TNC-NRG1 fusion in a non-small cell lung carcinoma [ 19 ] and in a papillary renal cell carcinoma [ 20 ], and TNC-USP6 fusion in a primary aneurysmal bone cyst [ 21 ]. In these scenarios, TNC is functioned as a strong promoter, leading to activation of oncogenes NRG1 and USP6 , and subsequently induction of tumor formation.…”

HER3 Is an Actionable Target in Advanced Prostate Cancer

“…We have, however, been unable to disprove ligand independent HER3 activation, but have demonstrated little evidence for autocrine tumor cell generation of the high affinity HER3 neuregulin ligands NRG1 and NRG2 by immunohistochemistry and RNAish in adenocarcinoma although our studies suggest that neuroendocrine PC cells may express NRG1. Furthermore, we could not identify any cases of NRG1 fusions/translocations in available mCRPC genomic data as has been suggested for other cancers and at least one case of prostate cancer (47).…”

Case Report: Disease progression of renal cell carcinoma containing a novel putative pathogenic KAT6A::NRG1 fusion on Ipilimumab- Nivolumab immunotherapy. A case study and review of the literature

“…Previously in RCC, three NRG1 fusion partners have been described: PCM1-NRG1 ( 16 ), RBPMS-NRG1 ( 1 ) and NRG1-TNC ( 17 ). In terms of tumour morphology, only the latter had been described, as an oncocytic papillary carcinoma with small nucleoli, not otherwise specified, sporadically showing cytoplasmic vacuolisation ( 17 ).…”

“…Previously in RCC, three NRG1 fusion partners have been described: PCM1-NRG1 ( 16 ), RBPMS-NRG1 ( 1 ) and NRG1-TNC ( 17 ). In terms of tumour morphology, only the latter had been described, as an oncocytic papillary carcinoma with small nucleoli, not otherwise specified, sporadically showing cytoplasmic vacuolisation ( 17 ). These appearances partly resemble focal areas identified in our case, but the full spectrum of histomorphology and immunoprofile were lacking in that study, so it is not possible to pinpoint distinct common features.…”