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. 2019 Aug 15;25(16):4966-4972.
doi: 10.1158/1078-0432.CCR-19-0160. Epub 2019 Apr 15.

Detection of NRG1 Gene Fusions in Solid Tumors

Sushma Jonna  1 , Rebecca A Feldman  2 , Jeffrey Swensen  2 , Zoran Gatalica  2 , Wolfgang M Korn  2 , Hossein Borghaei  3 , Patrick C Ma  4 , Jorge J Nieva  5 , Alexander I Spira  6 , Ari M Vanderwalde  7 , Antoinette J Wozniak  8 , Edward S Kim  9 , Stephen V Liu  10
Affiliations

Detection of NRG1 Gene Fusions in Solid Tumors

Sushma Jonna et al. Clin Cancer Res. .

Abstract

Purpose: NRG1 gene fusions are rare but potentially actionable oncogenic drivers that are present in some solid tumors. Details regarding the incidence of these gene rearrangements are lacking. Here, we assessed the incidence of NRG1 fusions across multiple tumor types and described fusion partners.

Experimental design: Tumor specimens submitted for molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)-certified genomics laboratory and that underwent fusion testing by anchored multiplex PCR for targeted RNA sequencing were retrospectively identified. The overall and tumor-specific incidence was noted, as was the specific fusion partner.

Results: Out of 21,858 tumor specimens profiled from September 2015 to December 2018, 41 cases (0.2%) harbored an NRG1 fusion. Multiple fusion partners were identified. Fusion events were seen across tumor types. The greatest incidence was in non-small cell lung cancer (NSCLC, 25), though this represented only 0.3% of NSCLC cases tested. Other tumor types harboring an NRG1 fusion included gallbladder cancer, renal cell carcinoma, bladder cancer, ovarian cancer, pancreatic cancer, breast cancer, neuroendocrine tumor, sarcoma, and colorectal cancer.

Conclusions: NRG1 fusions can be detected at a low incidence across multiple tumor types with significant heterogeneity in fusion partner.See related commentary by Dimou and Camidge, p. 4865.

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Conflict of interest statement

Conflict of Interest Statement: S. Jonna reports no competing interests. R.A. Feldman, J. Swensen, Z. Gatalica and W.M. Korn are employees of Caris Life Sciences. W.M. Korn reports consulting/advisory role from Merrimack and Merck Sharp & Dohme, stock/ownership interests with OncoCyte, has received honoraria from Genentech/Roche and institution-associated funding from Merrimack. H. Borghaei reports consulting/advisory role from Bristol-Myers Squibb, Lilly, Celgene, Genentech, Pfizer, Boehringer Ingelheim, EMD Serono, Trovagene, Novartis, Merck, AstraZeneca, Genmab, Regeneron, Contargia AB, BioNTech AG, Abbvie, received honoraria from Bristol-Myers Squibb, Celgene, Axiom Biotechnologies and institution-associated research funding from Millennium, Merck, Celgene, Bristol-Myers Squibb and Lilly. P.C. Ma reports association with the speakers’ bureau for Merck, Takeda, Bristol-Myers Squibb, stock/ownership from Cymeta Biopharmaceutical and institution-associated research funding from Pfizer, MedImmune, AstraZeneca, Bristol-Myers Squibb, Loxo, Xcovery, Abbvie, EpicentRx, Tesaro, Boehringer Ingelheim, OncoMed, CBT Pharmaceuticals, Merck and Cymeta Biopharmaceutical. J. Nieva reports consulting/advisory role with AstraZeneca, Genentech/Roche and Western Oncolytics, stock/ownership in Epic Sciences and research funding from Merck. A. Spira reports institution-associated research funding from Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, Abbvie, Ignyta, LAM Therapeutics, Trovagene, Takeda, Macrogenics and CytomX Therapeutics. A. Vanderwalde reports consulting/advisory role with Bristol-Myers Squibb, AstraZeneca, Genentech and Caris Life Sciences, has received honoraria from AstraZeneca and institution-associated research funding from Amgen, Merck, Genentech/Roche, Millennium, AstraZeneca, Polynoma, Lilly, Bristol-Myers Squibb and Amgen. A. Wozniak reports consulting/advisory role with Boehringer Ingelheim, AstraZeneca, ARIAD, Coherus Biosciences, Array BioPharma, Hospira, Quintiles, BeyondSpring Pharmaceuticals, WCCT Global, Epic, Huron Consulting, HUYA Bioscience International and Takeda and has received research funding from Boehringer Ingelheim. E.S. Kim reports consulting/advisory role with Lilly, AstraZeneca, Boehringer Ingelheim, Pfizer, Merck and Takeda, has received honoraria from Lilly, AstraZeneca, Boehringer Ingelheim, Pfizer, Merck and Takeda and research funding from Boehringer Ingelheim, Lilly, Merck, Ignyta and Genentech/Roche. S.V. Liu reports consulting/advisory role with Apollomics, Boehringer-Ingelheim, G1 Therapeutics, Genentech/Roche, Ignyta, Guardant 360, Inivata, Janssen, Pfizer, Lilly, Merck, Taiho Pharmaceutical, Bristol-Myers Squibb, AstraZeneca, Takeda, HERON and Regeneron and has received research funding from Genentech/Roche, Pfizer, Threshold Pharmaceuticals, Clovis Oncology, Corvus Pharmaceuticals, Esanex, Bayer, OncoMed, Merck, Lycera, AstraZeneca, Ignyta, Molecular Partners, Blueprint Medicines, Lilly and Rain Therapeutics.

Figures

Figure 1.
Figure 1.
Rate of NRG1 fusions by tumor type. The tumor type with NRG1 fusion in the other category is a neuroendocrine tumor of the nasopharynx. Abbreviations: GBC, gallbladder cancer (cholangiocarcinoma); PDAC, pancreatic ductal adenocarcinoma; RCC, renal cell carcinoma; NSCLC, non-small cell lung cancer; CRC, colorectal cancer.
Figure 2.
Figure 2.
Genomic features observed in NRG1-fusion positive solid tumors. Oncoprint plot illustrating co-occurrence of driver events, genes with any pathogenic variant detected in the cohort and other clinically relevant protein markers. Each NRG1-fusion positive sample corresponds to one row in the table: frame prediction of the fusion, cancer type and fusion partner are provided. Fill of boxes correlate with gene/protein status: (1) red, pathogenic variant detected or positive expression, (2) grey, wild type or low/negative expression and (3) white, test was not performed, or indeterminate. Pathogenic variants in oncogenes were rare, but at least one mutation in tumor suppressor genes including TP53 occurred in all but nine samples. Abbreviations: NSCLC, non-small cell lung cancer, TN (triple-negative) breast, HR+ (hormone receptor positive) breast, GBC, gallbladder cancer (cholangiocarcinoma); PDAC, pancreatic ductal adenocarcinoma; CRC, colorectal cancer; RCC, renal cell carcinoma; UC (urothelial bladder cancer); NET (neuroendocrine tumor of the nasopharynx); VUS, fusion variant of unknown significance; CDS, coding sequence.
Figure 3.
Figure 3.
NRG1 fusion partners. Pie chart showing the proportion and variety of fusion partners for NRG1.
Figure 4.
Figure 4.
Circos plot of depicting NRG1 fusion genes and partners from Table S1. NRG1 and partners in (A) NSCLC and (B) all other tumors
Figure 5.
Figure 5.
Schematic diagram of NRG1 fusion variants in solid tumors. A. Genomic structure of wild type NRG1; B. Fusion variants identified with 5’ partners joined to 3’ NRG1. Bars depict the predicted functional domains (not shown to scale) of interest and red dashed line indicates fusion breakpoints. The EGF domain is preserved in all fusion variants.
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