Frequent <i>NRG1</i> fusions in Caucasian pulmonary mucinous adenocarcinoma predicted by Phospho-ErbB3 expression

Trombetta, Domenico; Graziano, Paolo; Scarpa, Aldo; Sparaneo, Angelo; Rossi, Giulio; Rossi, Antonio; Maïo, Massimo Di; Antonello, Davide; Mafficini, Andrea; Fabrizio, Federico Pio; Manzorra, Maria C.; Balsamo, Teresa; Centra, Flavia; Simbolo, Michele; Pantalone, Angela; Notarangelo, Michela; Parente, Paola; Dimitri, M; Bonfitto, Antonio; Fiordelisi, Fabiola; Storlazzi, Clelia Tiziana; L’Abbate, Alberto; Taurchini, Marco; Maiello, Evaristo; Fazio, Vito Michele; Muscarella, Lucia Anna

doi:10.18632/oncotarget.23800

Cited by 38 publications

(37 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tp53 (50%) and pTEN loss are two common co-mutations. 130,131 NRG1 is a natural ligand for HER-3, which leads to dimerization and activation of HER-2 and HER-3 followed by PI3K/AKT 129,131 . These findings support targeting NRG1 fusion with a pan-HER inhibitor.…”

Section: Neuregulin-1 Fusionmentioning

confidence: 99%

Targeting non-small cell lung cancer: driver mutation beyond epidermal growth factor mutation and anaplastic lymphoma kinase fusion

Chu

2020

Ther Adv Med Oncol

View full text Add to dashboard Cite

The identification of driver mutations in epidermal growth factor receptor, anaplastic lymphoma kinase, the BRAF and ROS1 genes and subsequent successful clinical development of kinase inhibitors not only significantly improves clinical outcomes but also facilitates the discovery of other novel driver mutations in non-small cell lung cancer. These driver mutations can be categorized into mutations in or near the kinase domain, gene amplification or fusion. In this review, BRAF V600E, EGFR and HER-2 exon 20 mutation, FGFR1–4, K-RAS, MET, neuregulin-1, NRTK, PI3K/AKT/mTOR, RET and ROS1 gene aberration and their therapeutics will be discussed.

show abstract

Section: Neuregulin-1 Fusionmentioning

confidence: 99%

Targeting non-small cell lung cancer: driver mutation beyond epidermal growth factor mutation and anaplastic lymphoma kinase fusion

Chu

2020

Ther Adv Med Oncol

View full text Add to dashboard Cite

show abstract

“…The GR method is based on exchange resins methodology and used the following standard protocol from Qiagen [24]. FFPE sections for each sample were scraped and re-suspended in a sterile tube with 160 μL of deparaffinization solution for 3′ at 56 °C to remove the excess paraffin.…”

Section: Methodsmentioning

confidence: 99%

Automated Workflow for Somatic and Germline Next Generation Sequencing Analysis in Routine Clinical Cancer Diagnostics

Muscarella

Fabrizio

Bonis

et al. 2019

Cancers

View full text Add to dashboard Cite

Thanks to personalized medicine trends and collaborations between industry, clinical research groups and regulatory agencies, next generation sequencing (NGS) is turning into a common practice faster than one could have originally expected. When considering clinical applications of NGS in oncology, a rapid workflow for DNA extraction from formalin-fixed paraffin-embedded (FFPE) tissue samples, as well as producing high quality library preparation, can be real challenges. Here we consider these targets and how applying effective automation technology to NGS workflows may help improve yield, timing and quality-control. We firstly evaluated DNA recovery from archived FFPE blocks from three different manual extraction methods and two automated extraction workstations. The workflow was then implemented to somatic (lung/colon panel) and germline (BRCA1/2) library preparation for NGS analysis exploiting two automated workstations. All commercial kits gave good results in terms of DNA yield and quality. On the other hand, the automated workstation workflow has been proven to be a valid automatic extraction system to obtain high quality DNA suitable for NGS analysis (lung/colon Ampli-seq panel). Moreover, it can be efficiently integrated with an open liquid handling platform to provide high-quality libraries from germline DNA with more reproducibility and high coverage for targeted sequences in less time (BRCA1/2). The introduction of automation in routine workflow leads to an improvement of NGS standardization and increased scale up of sample preparations, reducing labor and timing, with optimization of reagents and management.

show abstract

“…p-ERBB3 IHC also had a sensitivity of 94% and a specificity of 100% among 51 IMA samples and 100% sensitivity and 94% specificity among 34 non-IMA adenocarcinoma samples when using FISH as the method for comparison. 16 The majority of NRG1þ NSCLC cases have IMA histology (Fig. 1B), but IMA accounts for only 5% of lung adenocarcinoma.…”

mentioning

confidence: 95%

“…1C). 2,[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] In one report, the presence of NRG1 fusions confers a poor survival among mucinous lung adenocarcinoma. 14 Given the rarity of NRG1þ NSCLC, a basic understanding of the genomic structure of the NRG1 will help our appreciation of the potential complexities in detecting NRG1þ NSCLC.…”

mentioning

confidence: 99%

“…8,9,13 Patients who have NRG1þ NSCLC have been treated with afatinib that inhibits the kinase activity of EGFR/ HER2 or HER3 monoclonal antibodies that can block ligand-dependent activation of HER3 and subsequent hetero-dimerization with EGFR, HER2, and HER4 with mixed success ( Table 2). [13][14][15][16][17] Drilon et al 13 reported one patient with NRG1þ NSCLC achieving the longest duration of response among all of the case reports (19 months) with an anti-HER3 monoclonal antibody that both inhibit NRG1 binding to HER3 and HER3 heterodimerization and can mediate antibodydependent cellular cytotoxicity. 13,27,28 Many monoclonal mono-(HER3) or bi-specific HER2/HER3 monoclonal antibodies are in clinical development that could potentially be used to target NRG1þ fusions.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Neuregulin 1 Fusion–Positive NSCLC

Nagasaka

2019

Journal of Thoracic Oncology

View full text Add to dashboard Cite

In the past decade, we have witnessed the identification of multiple actionable driver mutations in NSCLC encompassing the four major modes of genetic alterations: point mutations, insertions/deletions (indels), gene amplification, and gene fusions primarily involving receptor tyrosine kinase (RTK) receptors. 1 In 2014, the first neuregulin 1 (NRG1) fusion in NSCLC was reported by Fernandez-Cuesta et al. 2 when they identified five CD74-NRG1 fusions in invasive mucinous adenocarcinoma (IMA) of the lung. Physiologically, NRG1 is proteolytically cleaved and secreted and is involved in the diverse spectrum of cellular process primarily but not limited to neural development. 3 The CD74-NRG1 fusion provides an extracellular anchor for the epidermal growth factor (EGF) domain of NRG1 to bind to erb-b2 receptor tyrosine kinase 3 (HER3) leading to HER3 heterodimerization and activation of downstream signaling pathways leading to oncogenesis. 4 NRG1 fusions thus represent a novel mechanism of generating ligand proximity to the natural occurring wild-type RTKs that is distinct from the oligomerization of rearranged RTK kinase domains we are now familiar with. 5 Overall, NRG1 fusions are relatively rare. The incidence of NRG1þ fusions is estimated to be at 0.2% (41 positive cases) from a recent large scale survey of 21,858 cases of solid malignancies using RNA sequencing which is generally considered to be the gold standard to dettect rare gene fusions. Although the vast majority of the NRG1þ fusion cases are found in NSCLC (61%, 25 of 41), NRG1þ NSCLC only constitutes 0.3% of all NSCLC samples tested. 6 After the initial report of CD74-NRG1 NSCLC, three more groups in rapid succession all reported the identification of NRG1 fusions in NSCLC and extended the NRG1 fusions variants to solute carrier family 3 member 2 (SLC3A2)-NRG1, syndecan 4 (SDC4)-NRG1, RNA binding protein, mRNA processing factor (RBPMS)-NRG1, and WRN RecQ like helicase (WRN)-NRG1 in 2014. [7][8][9] The identification of WRN-NRG1 extended the presence of NRG1 fusion to squamous cell lung cancer. 9 To date, there are 17 fusion partners identified in NRG1þ NSCLC (Table 1) with the CD74-NRG1 fusion variant as the most common in NSCLC followed by SLC3A2-NRG1 and SDC4-NRG1 (Fig. 1A) in published literature. 2,[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] It is important to note that many of the fusion partners identified in other non-NSCLC NRG1þ solid tumors by Jonna and colleagues remained to be identified in NRG1þ NSCLC. Hence the number of NRG1þ NSCLC fusion partners is sure to increase in the future. 6 Of note, among the 15 SLC3A2-NRG1 fusions reported in the literature so far, 13 were identified in Asian patients (12 from Korea, and 1 from Japan). The majority of the patients with NRG1þ NSCLC had IMA histology with squamous cell carcinoma hisology (LUSC) accounting for 6% ( Fig. 1B). 2,[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] The majority of patients with NRG1þ NSCLC with known smoking status were never-smo...

show abstract

Frequent NRG1 fusions in Caucasian pulmonary mucinous adenocarcinoma predicted by Phospho-ErbB3 expression

Cited by 38 publications

References 30 publications

Targeting non-small cell lung cancer: driver mutation beyond epidermal growth factor mutation and anaplastic lymphoma kinase fusion

Targeting non-small cell lung cancer: driver mutation beyond epidermal growth factor mutation and anaplastic lymphoma kinase fusion

Automated Workflow for Somatic and Germline Next Generation Sequencing Analysis in Routine Clinical Cancer Diagnostics

Neuregulin 1 Fusion–Positive NSCLC

Contact Info

Product

Resources

About