A recent publication, featuring the Director of the Biomarker Discovery Program at the Center for Individualized Medicine at Mayo Clinic, George Vasmatzis, examining the role of ASCL1 in the neuroendocrine differentiation of lung adenocarcinoma.
The clinical significance of neuroendocrine differentiation in lung adenocarcinoma, and the most appropriate biomarkers for this assessment, has long been debated. In the absence of a gold standard, investigators have most commonly used immunohistochemical staining of one or a combination of neuroendocrine markers, such as chromogranin, synaptophysin, neuron-specific enolase or neural cell adhesion molecule (CD56/NCAM) to assess the role of neuroendocrine differentiation in lung cancer survival. Notably, previous reports have not included ASCL1, despite the pivotal role this gene has in the development of neuroendocrine cells in the lung.
We examined ASCL1 expression in lung cancer samples of varied histologic subtype, clinical outcome and smoking status and compared with expression of traditional NE markers. ASCL1 mRNA expression was found almost exclusively in smokers with AD, in contrast to non-smokers and other lung cancer subtypes. ASCL1 protein expression by immunohistochemical analysis correlated best with synaptophysin compared with chromogranin and CD56/NCAM.
Analysis of a compendium of 367 microarray-based gene expression profiles in stage I lung adenocarcinomas identified significantly higher expression levels of the RET oncogene in ASCL1-positive tumors (ASCL1+) compared with ASCL1- tumors (q-value <10-9). High levels of RET expression in ASCL1+ but not in ASCL1- tumors was associated with significantly shorter overall survival (OS) in stage 1 (P=0.007) and in all AD (P=0.037). RET protein expression by IHC had an association with OS in the context of ASCL1 expression. In silico gene set analysis and in vitro experiments by ASCL1 shRNA in AD cells with high endogenous expression of ASCL1 and RET implicated ASCL1 as a potential upstream regulator of the RET oncogene.
Also, silencing ASCL1 in AD cells markedly reduced cell growth and motility. These results suggest that ASCL1 and RET expression defines a clinically relevant subgroup of ∼10% of AD characterized by NE differentiation.