Image: Immunohistochemical analysis of pulmonary adenocarcinoma stained for ASCL1 (Photo courtesy of LifeSpan BioSciences).
A specific pair of proteins may be a successful prognostic biomarker for identifying smoking-related lung cancers, especially pulmonary adenocarcinoma.
The protein achaete-scute homolog 1 (ASCL1) is an important regulatory transcription factor in pulmonary neuroendocrine (NE) cell development, but its value as a biomarker of NE differentiation and as a potential prognostic biomarker remains unclear.
Scientists at the Mayo Clinic (Rochester, MN, USA) 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 messenger ribonucleic acid (mRNA) expression was found almost exclusively in smokers with adenocarcinoma, in contrast to nonsmokers and other lung cancer subtypes.
Analysis of a compendium of 367 microarray-based gene expression profiles in stage I lung adenocarcinomas identified significantly higher expression levels of the rearranged during transfection (RET) oncogene in ASCL1-positive tumors (ASCL1+) compared with ASCL1− tumors. ASCL1 protein expression by immunohistochemical (IHC) analysis correlated best with synaptophysin compared with chromogranin and the cluster of differentiation CD56 and the neural cell adhesion molecule (CD56/NCAM).
High levels of RET expression in ASCL1+, but not in ASCL1- tumors, was associated with significantly shorter overall survival in stage 1 and in all adenocarcinomas. RET protein expression by IHC had an association with overall survival in the context of ASCL1 expression. When scientists blocked the ASCL1 protein in lung cancer-cell lines expressing both genes, the level of RET decreased and tumor growth slowed. This leads them to believe this mechanism will be a promising target for potential drugs and a strong candidate for clinical trials.
George Vasmatzis, PhD, molecular medical scientist and senior author on the study, said “This is exciting because we’ve found what we believe to be a ‘drugable target’ here. It’s a clear biomarker for aggressive adenocarcinomas. These are the fast-growing cancer cells found in smokers’ lungs.” The study was published on September 16, 2013, in the journal Oncogene.