P2.01-094 Stromal Antigen 1 (SA-1), a Cohesin, is a Novel Proto-Oncogene Regulating Chromatin in Non-Small Cell Lung Cancer (NSCLC)

Abstract

The molecular composition NSCLC is heterogeneous and clinically manifested as differential therapeutic responsiveness. It is increasingly appreciated that changes in high order chromatin (HOC) structure may play an important role in controlling gene expression and may be one of the fundamental events in carcinogenesis. However, while several HOC regulators are altered in lung cancer (e.g. Arid1a) from the cancer genome atlas work (TCGA), these occur in a minority of tumors suggesting involvement of other modulators. Recently, SA-1 (Stag-1), a member of the cohesin family, has been shown to be a HOC regulator in cancer via controlling chromatin looping and hence gene expression. Since no previous reports on cohesin in lung cancer, we therefore, focused on the role of SA-1 in NSCLC. We performed immunohistochemical analysis (IHC) of 190 cancers and compared to benign tissue through standard techniques. We also extracted SA-1 data from the TCGA databases (Nature 2012 & 2014). SA-1 was markedly (∼2-3 fold) overexpressed in all types of NSCLC (p<0.01) versus benign tissue (Figure 1). This increase was striking at stage 1 NSCLCs with minimal further increase noted at higher stages. TCGA data demonstrated amplification/mutation in ∼17% of squamous but only 3% of adenocarcinomas. This suggested that epigenetic regulations was paramount. Kaplan-Meier analysis showed major impact of SA-1 alterations on survival. For instance, in squamous cancers, median disease-free survival with versus without SA-1 amplification was 8 vs 38 months, respectively. We show for the first time that SA-1 is overexpressed early in NSCLC consonant with status as a proto-oncogene. This upregulation occurs predominantly epigenetic with some contributions with genetic factors. Moreover, SA-1 may have important prognostic markers underscoring its importance of HOC regulation in NSCLC. Further studies are ongoing to elucidate the precise role of SA-1 in the pathogenesis and natural history of NSCLC.