Abstract 2495: RUNX1T1 is amplified in combined small cell lung cancer
Authors: He Tian , McColl Karen , Savadelis Alyssa , Chen Yanwen , Wildey Gary , Dowlati Afshin 
Published: August 2018

Small cell lung cancer (SCLC) is a highly aggressive malignancy that expresses neuroendocrine (NE) genes and represents approximately 15% of all lung cancers; the remaining histological subtype is non-small cell lung cancer (NSCLC). Clinically, there are two types of SCLC, termed ‘pure' and ‘combined'. Combined SCLC presents as a mixture of SCLC and NSCLC components within the same tumor mass. We analyzed 88 SCLC patient tumors by targeted exome sequencing and found that four SCLC patients demonstrated RUNX1T1 amplification. Interestingly, among these 88 SCLC patients there were two with combined SCLC and both demonstrated RUNX1T1 amplification only in the small cell component. Neither MYC (8p24) nor FGFR1 (8p11), two genes commonly amplified in SCLC that are nearby the RUNX1T1 locus (8p22), were co-amplified. RUNX1T1, also called ETO or MTG8, was first identified in the oncogenic fusion transcript AML1/ETO in acute myelogenous leukemia (AML) and was previously reported as a transcriptional co-repressor. Based on our observation we hypothesized that: 1) RUNX1T1 may be a specific marker for SCLC and may play a role in determining the SCLC phenotype, including NE expression, and 2) RUNX1T1 may play a role in transforming NSCLC to SCLC in the early stages of combined SCLC tumor formation. First we examined RUNX1T1 mRNA expression among cancer cell lines using the CCLE database and found that RUNX1T1 is highly expressed in SCLC cells compared to other cancer cells, especially NSCLC cells. This was also true in tumors using RNAseq data. Consistent with these mRNA profiles, our western blot results showed higher RUNX1T1 protein expression in SCLC compared to NSCLC cell lines. These findings validate that RUNX1T1 expression is specifically upregulated in SCLC compared to NSCLC. To investigate a role for RUNX1T1 in determining the SCLC phenotype, we overexpressed RUNX1T1 in SCLC cell lines by lentiviral transduction and observed marked growth suppression in H82, H2171, and H841 cells. Conversely, transient knock down of RUNX1T1 expression in the SCLC cell line H446 using siRNA decreased the expression of two NE proteins (NEUROD1 and TTF1). To explore a potential role of RUNX1T1 in NSCLC to SCLC transformation, we overexpressed RUNX1T1 in three NSCLC cell lines (PC-9, H1650 and A549) but observed no obvious phenotypic changes and no increase in NE gene expression. In conclusion, we have demonstrated that RUNX1T1 expression is upregulated in SCLC compared to NSCLC. Moreover, the results from RUNX1T1 overexpression and knockdown experiments in SCLC cell lines indicates a potential role of RUNX1T1 in regulating the SCLC phenotype and NE expression.

Citation Format: Tian He, Karen McColl, Alyssa Savadelis, Yanwen Chen, Gary Wildey, Afshin Dowlati. RUNX1T1 is amplified in combined small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2495.