Abstract
NRG1 fusions were recently reported as a new molecular feature of Invasive Mucinous Adenocarcinoma (IMA) of the lung. The NRG1 chimeric ligand acts as a strong inductor of phosphorylation and tyrosine kinase activity of the ErbB2/ErbB3 heterodimer, thus enhancing the PI3K–AKT/MAPK pathways. The NRG1 fusions were widely investigated in Asian IMA cohorts, whereas just anecdotal information are available about the occurrence of NRG1 fusions in IMA Caucasian population.Here we firstly explored a large Caucasian cohort of 51 IMAs and 34 non-IMA cases for the occurrence of NRG1 rearrangements by fluorescent in situ hybridization (FISH) and RNA target sequencing. FISH results were correlated to the immunohistochemical expression of phosphorylated-ErbB3 (pErbB3) receptor and the mutational status of KRAS, EGFR and ALK genes.The NRG1 rearrangements were detected in 31% IMAs and 3% non-IMAs and the CD74-NRG1 fusion transcript variant was characterized in 4 NRG1-positive IMAs. Moreover, pErbB3 expression was found to be strictly associated to the mucinous pattern (p = 0.012, Chi-square test) and all IMA cases showing aberrant expression of pErbB3 demonstrated NRG1 rearrangements. No significant correlation between NRG1 rearrangements and EGFR, KRAS or ALK mutations respectively, was observed.We report for the first time that NRG1 fusions are driver alterations clearly associated with mucinous lung adenocarcinoma subtype of Caucasian patients and not exclusive of Asiatic population. pErbB3 immunostaining may represent a strong predictor of NRG1 fusions, pointing out the detection of pErbB3 by IHC as a rapid and effective pre-screening method to select the NRG1-positive patients.
Highlights
The aberrant activation of members of the family of epidermal growth factor receptor tyrosine kinases (EGFR/ ERBB) has been implicated in cancer development and progression
The results of our study can be summarized as follows: i) NRG1 rearrangements are firstly well described in a cohort of Caucasian lung adenocarcinoma patients and represent a feature of pulmonary Invasive Mucinous Adenocarcinoma (IMA); ii) prevalence of NRG1 fusions in Caucasian patients is similar to that reported in Asian population; iii) pErbB3 immunostaining is a strong predictor of NRG1 fusions; iv) NRG1 rearrangements are not mutually exclusive to KRAS mutations in IMAs in Caucasian patients
NRG1 fusion genes in lung adenocarcinoma have been reported for the first time in 4 of 15 (27%) Asiatic IMAs [9]
Summary
The aberrant activation of members of the family of epidermal growth factor receptor tyrosine kinases (EGFR/ ERBB) has been implicated in cancer development and progression. Mutations of epidermal growth factor receptor (EGFR) are a predictive marker of response to tyrosine kinase inhibitors (TKIs). The deregulation of ErbB2/ErbB3 machinery is emerging as an oncogenic trait of lung adenocarcinoma with mucinous pattern, a tumor subtype that is otherwise associated with KRAS mutations [5]. The chimeric CD74NRG1 (Cluster of Differentiation 74-Neuregulin-1) gene derived by the chromosome 8 rearrangement is recently reported as the first potentially treatable oncogenic driver alteration associated with this specific pattern of lung adenocarcinoma. NRG1 rearrangements accounted for a large portion of Invasive Mucinous Adenocarcinoma (IMA) of the lung [9] of Asian patients, both in KRAS-wild type and KRAS mutated tumors. Three Caucasian cases of IMA have been investigated for NRG1 rearrangements by fluorescent in situ hybridization (FISH) and resulted negative [10]
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