Characterization of NRG1 gene fusion events in solid tumors.

Authors

Sushma Jonna

Sushma Jonna

Georgetown Lombardi Comprehensive Cancer Center, Washington, DC

Sushma Jonna , Rebecca Feldman , Sai-Hong Ignatius Ou , Misako Nagasaka , Jeffrey Swensen , Wolfgang Michael Korn , Hossein Borghaei , Ari M. Vanderwalde , Gilberto Lopes , Jorge J. Nieva , Alexander I. Spira , Edward S. Kim , Stephen V. Liu

Organizations

Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, Caris Life Sciences, Phoenix, AZ, Chao Family Comprehensive Cancer Center, University of California Irvine, Orange, CA, Barbara Ann Karmanos Cancer Institute, Detroit, MI, University of California San Francisco, San Francisco, CA, Fox Chase Cancer Center, Philadelphia, PA, The University of Tennessee Health Science Center, West Cancer Center, Germantown, TN, University of Miami Health System, Miami, FL, University of Southern California, Los Angeles, CA, Virginia Cancer Specialists, Fairfax, VA, Levine Cancer Institute/Atrium Health, Charlotte, NC, Georgetown University, Washington, DC

Research Funding

No funding received
None

Background: NRG1 fusions are actionable genomic alterations detected across tumor types. The NRG1 gene encode for neuregulin, which serves as a ligand for ERBB3 and ERBB4 receptors and activates downstream signaling through the MAPK and PI3K pathways. Here, we update the detection of NRG1 gene fusions across tumor types and further describe fusion characteristics. Methods: Samples submitted for clinical molecular profiling that included RNA-sequencing (Archer Dx or Caris MI transcriptome) were retrospectively analyzed for NRG1 fusion events. All NRG1 fusions with ≥ 3 junction reads were identified for manual review and for characterization of fusion class, intact functional domains, domain prediction, breakpoints, frame retention and co-occurring alterations by NGS. Results: A total of 82 NRG1 fusion events (0.2% of 44,570) were identified. Among the fusions identified, the distribution across tumor types was as follows: non-small cell lung cancer (NSCLC, 54%), breast cancer (11%), ovarian cancer (7%), pancreatic cancer (7%), cholangiocarcinoma (6%), colorectal cancer (5%), and other (10%). Forty-two unique fusion partners were identified, the most common being CD74 (23%), ATP1B1 (9%), SLC3A2 (7%), RBPMS (6%) and SDC4 (4%). Almost half (47%) of all fusion events are expected to include the transmembrane domain contributed by the NRG1 fusion partner. Lung and pancreatobilliary cancers had the highest rates of transmembrane domain retention from their fusion partners (63.6% and 54.5%, respectively). In all other tumor groups, most fusion partners lacked transmembrane domains. In 15% of cases, the chimeric transcripts are predicted to lead to increased expression of NRG1. The most commonly reported breakpoints in NRG1 occur in exon 6 and exon 2. While fusions with the NRG1 breakpoint at exon 2 retain the immunoglobulin (Ig) domain and all downstream portions (including EGF-like domain), those at exon 6 do not contain the Ig portion and result in shorter chimeric proteins. The breakpoints in all CD74:NRG1 fusions, the most common fusions in NSCLC, occur at exon 5 or 6 and cause truncation of domains upstream of the EGF-like domain. In ATP1B1:NRG1 fusions, the most common fusions in pancreatobilliary cancers, the breakpoints are at exon 1 or 2 and retain the Ig domain. Conclusions:NRG1 fusion products are diverse across tumor types, but the significance of these variations is not clear. The biological and clinical implications of retaining certain domains of NRG1 (such as the Ig domain) and of fusion partners warrants further investigation.

Disclaimer

This material on this page is ©2024 American Society of Clinical Oncology, all rights reserved. Licensing available upon request. For more information, please contact licensing@asco.org

Abstract Details

Meeting

2020 ASCO Virtual Scientific Program

Session Type

Poster Session

Session Title

Developmental Therapeutics—Immunotherapy

Track

Developmental Therapeutics—Immunotherapy

Sub Track

New Targets and New Technologies (IO)

Citation

J Clin Oncol 38: 2020 (suppl; abstr 3113)

DOI

10.1200/JCO.2020.38.15_suppl.3113

Abstract #

3113

Poster Bd #

177

Abstract Disclosures

Similar Abstracts

Abstract

2023 ASCO Annual Meeting

NRG1 fusions in solid tumors.

First Author: Brinda Gupta

Abstract

2022 ASCO Annual Meeting

CRESTONE: Initial efficacy and safety of seribantumab in solid tumors harboring NRG1 fusions.

First Author: Daniel R. Carrizosa

First Author: Alison M. Schram

First Author: Alison M. Schram