Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to deregulated activity.
NRG1 fusions are oncogenic gene fusions involving the neuregulin-1 (NRG1) gene, which result from structural DNA rearrangements.
Fusions involving the neuregulin-1 gene (NRG1) result in ErbB-mediated pathway activation and is a candidate for targeted treatment.
The most frequently reported NRG1 fusion is CD74-NRG1, which most commonly occurs in patients with invasive mucinous adenocarcinomas (IMA) of the lung.
Other NRG1 fusions occur in patients with lung cancer, including ATP1B1, SDC4, and RBPMS.
NRG1 fusions are also present in patients in other solid tumors, such as pancreatic ductal adenocarcinoma (PDAC).
NRG1 fusions are rare across different types of cancer, with a reported incidence of <1%.
Mucinous adenocarcinomas of the lung represents ≈2‒10% of lung adenocarcinomas and has a reported incidence of ≈10‒30% for NRG1 fusions.
A substantial proportion (≈20%) of NRG1 fusion-positive non-small-cell lung cancer (NSCLC) cases are non-mucinous adenocarcinomas.
ErbB-targeted treatments, such as afatinib, a pan-ErbB tyrosine kinase inhibitor, are therapeutics in patients harboring NRG1 fusions.
Gene fusions are hybrid genes that result from structural DNA rearrangements including translocations and insertions, transcription read-through, or splicing.
Oncogenic gene fusions result in deregulated activity.
Oncogenic gene fusions are the driver events responsible for initiation and maintenance of various types of cancer.
For some cancers driven by gene fusions, respond to targeted therapies: tyrosine kinase inhibitors (TKI) such as imatinib, dasatinib and nilotinib have markedly improved outcomes in patients with chronic myeloid leukemia (CML), which is driven by the BCR-ABL1 tyrosine kinase, a fusion protein created by a chromosomal translocation.
TKIs targeting these driver fusions: anaplastic lymphoma kinase (ALK) protein; ALK TKIs have been shown to be highly effective in ALK-rearranged lung adenocarcinomas, leading to dramatic improvement of survival rate.
ALK fusions are also found in other tumors, albeit at a lower frequency than in non-small-cell lung cancer (NSCLC).
Other targetable fusions ROS1 in NSCLC.
RET in thyroid malignancies and in NSCLC, and the three neurotrophic receptor tyrosine kinase genes (NTRK1, NTRK2, and NTRK3) that can undergo chromosomal rearrangements leading to functional gene fusions.
NRG1 fusions are present at a low incidence in multiple tumor types but are enriched in invasive mucinous adenocarcinomas of the lung.
NRG1 fusions result in aberrant expression of the Epidermal Growth Factor (EGF)-like domain of neuregulin-1 (NRG1) on the cell surface, which serves as a ligand for ErbB3 (HER3) and induces the formation of heterodimers, most frequently ErbB2-ErbB3, but also with EGFR (ErbB1) and ErbB4.
NRG1 fusions leads to pathologic activation of the phosphoinositide 3-kinase-protein kinase B (PI3K-AKT), mitogen-activated protein kinase (MAPK), and other signaling pathways, resulting in abnormal cell proliferation.
NRG1 fusions and the subsequent ErbB-mediated constitutive pathway activation represents a therapeutic target.
The ErbB family of receptor tyrosine kinases is composed of four members (EGFR, ErbB2 [HER2], ErbB3, and ErbB4).
There are 13 extracellular ligands for the ErbB family members, which can be divided into those that bind EGFR and ErbB4.
Those that bind ErbB3 and ErbB4 are known as the neuregulins and comprises four members (NRG1–4).
NRG1 and NRG2 bind to ErbB3, and NRG1‒4 bind to ErbB4.
Upon ligand binding, these receptors form homo- or heterodimers, which results in phosphorylation and activation of the PI3K-AKT, MAPK, and other pathways.
The NRG1 gene is located on chromosome 8 and encodes NRG.
These fusions lead to the activation of the ErbB (HER) family of receptor tyrosine kinases, particularly HER3, through the EGF-like domain of NRG1.
NRG1 binding to ErbB3 can induce heterodimerization, preferentially with the ErbB2 receptor, allowing ErbB2 to phosphorylate the kinase-defective ErbB3 and leads to activation of downstream pathways including the PI3K-AKT and MAPK pathways.
NRG1 also has the capacity to bind ErbB4, similarly leading to dimerization as either a homodimer or a heterodimer with ErbB2/ErbB3, and subsequent activation.
Different ErbB homo- and heterodimers activate different pathways to different degrees.
This activation induces heterodimerization with HER2, subsequently triggering downstream signaling pathways such as PI3K-AKT and MAPK, which promote tumorigenesis.
NRG1 fusions are relatively rare, with an incidence of less than 1% across various solid tumors, including non-small cell lung cancer (NSCLC), breast cancer, pancreatic ductal adenocarcinoma, and others.
The most common NRG1 fusion partner is CD74, but other partners like ATP1B1, SDC4, and RBPMS have also been identified.
Detection of NRG1 fusions techniques such as fluorescence in situ hybridization (FISH), immunohistochemistry, and next-generation sequencing (NGS) are employed, with RNA sequencing being the most sensitive method.
NRG1 fusion-positive tumors may respond to ErbB-targeted treatments.
Afatinib, a pan-ErbB tyrosine kinase inhibitor, has shown promise in clinical trials.
Activated receptors dimerize, forming ErbB3- or ErbB4-containing homo- or hetero ErbB dimers, preferentially involving ErbB2.
NRG1-fusion proteins hold the EGF-like domain cause uncontrolled juxtacrine signaling.
Aberrant NRG1 signaling drives cell proliferation and avoidance of apoptosis via PI3K and RAS dependent signaling and activation of downstream signalling molecules.
NRG1-fusion proteins may also drive autocrine signaling via the PI3K/Ras dependent pathways.
Fusion proteins and genes in solid tumors were detected primarily using immunohistochemistry and fluorescence in situ hybridization (FISH) techniques.
Advances in gene fusion detection include DNA next-generation sequencing (NGS) and the introduction of targeted gene fusion panels on RNA.
PCR for targeted RNA sequencing’s sensitivity and specificity better than standard FISH assays
Overall, RNA sequencing may be more reliable than DNA NGS at detecting NRG1 fusions.
NRG1 fusions are rare across different types of cancer, typically occurring in <1% in most reported series.
DNA NGS, detected NRG1 rearrangements in 3 of 2,079 patients (0.14%) with lung adenocarcinomas, 1 of 791 patients (0.13%) with pancreatic adenocarcinoma, and 1 of 2,703 patients (0.04%) with breast carcinoma.
The Cancer Genome Atlas identified NRG1 rearrangements across various tumor histologies, as follows: breast (AKAP13-NRG1: 0.01%); head and neck cancer (THBS1-NRG1 and PDE7A-NRG1: 0.49%); lung adenocarcinoma (SDC4-NRG1: 0.22%); renal clear cell carcinoma (PCM1-NRG1: 0.19%); squamous cell lung cancer (THAP7-NRG1 and SMAD4-NRG1: 0.21%); ovarian cancer (RAB3IL1-NRG1: 0.24%); pancreatic cancer (ATP1B1-NRG1: 0.55%); uterine carcinosarcoma (NRG1-PMEPA1: 1.75%), and prostate cancer (NRG1-STMN2: 0.3%).
Other NRG1-postive tumor types included gallbladder cancer, renal cell carcinoma, bladder cancer, ovarian cancer, pancreatic cancer, breast cancer, neuroendocrine tumor, sarcoma, and colorectal cancer.
KRAS mutations are the most frequent oncogenic driver mutations in invasive mucinous adenocarcinomaa occurring in 28‒87% of cases.
Concurrent NRG1 rearrangements with KRAS mutations occur in 33% of mucinous adenocarcinomas of the lung.
Almost all patients harboring NRG1 fusions are KRAS wild-type, which provides a useful screening strategy for identifying pancreatic duct cancers on patients with NRG1 fusions.
Initial reports of NRG1 fusions in patients with invasive mucinous (IMA) adenocarcinoma of the lung indicated that most of the patients were female and never smokers and much of the work was done in an East Asian population.
A recent evaluation of a cohort of 85 Caucasian lung cancer patients found NRG1 rearrangements in 31% of patients with IMA and 3% of those with non-IMA.22
These findings indicate that NRG1 fusions are important drivers of IMA in both Asian and Caucasian populations.
Moreover, recent results from the international NRG1 registry indicate a substantial proportion (≈20%) of NRG1-positive NSCLC are non-mucinous adenocarcinomas, and there were also cases of non-adenocarcinoma NSCLC.
The prognostic value of NRG1 fusions in IMA is unclear.
As noted earlier, NRG1 fusions may lead to cancer stem cell formation, and CSCs are known to be related to tumor recurrence and metastasis, chemo-resistance and poor prognosis.
Patients with IMA, patients harboring tumors with NRG1 fusions had a significantly shorter overall survival (OS) than those without NRG1 fusions (median 51.9 months vs. not reached; p=0.019).
However, other studies report that OS was no worse in patients with mucinous compared with non-mucinous lung adenocarcinoma, and that there was no difference in prognosis for patients with gene fusions.