Abstract 287: Deletion of 3p22.1 by FISH in non-small cell lung cancer (NSCLC) is significantly correlated with loss of β-catenin membrane expression and dysregulated cell adhesion.

The role of WNT signaling is well established in lung cancer and numerous studies have shown that loss/reduction in expression of β catenin, a key regulator of this pathway, is related to dysregulated cell adhesion, epithelial-mesenchymal transformation (EMT) and poor survival. A recent genome-wide association study (GWAS) in patients with advanced NSCLC and receiving platinum-based therapy showed that a SNP involving 3p22.1 (rs7629386) situated close to β catenin (CTNNB1) was associated with worse survival. In prior studies we have shown that deletion 3p22.1 (del 3p) was frequently involved in early events of lung cancer pathogenesis. The fluorescent in situ hybridization (FISH) BAC probe for 3p22.1 used in our studies is closely adjacent to CTNNB1. We therefore hypothesized that del 3p might involve a concurrent deletion of CTNNB1, and hence would be associated with reduced β catenin expression. Tumor microarrays (TMAs) from 145 NSCLC patients, 107 early stage (I and II) and 38 advanced stage (III and IV), were reacted with anti-β catenin antibody and scored in triplicate. Normal staining was defined as complete membranous or partial membranous with/ without cytoplasmic staining in >90% of tumor cells, and all others were classified as reduced. FISH performed on bronchoscopic brush biopsies: ipsilateral to tumor (TBB), contralateral to tumor (NBB), normal lung (NTP), tissue adjacent to tumor (TAB), and tumor touch preparations (TTP) were evaluated for del 3p by comparing to an internal centromeric probe. A logistic regression model was used to assess the relationship between del 3p at the different sites and β catenin expression. TMAs were also evaluated for Ki-67 by immunohistochemistry. A Cox proportional hazard model was used to assess for overall survival by del 3p at the different sites and Ki-67 proliferation index. Of the 145 cases, 113 stained normal and 32 had reduced staining. Statistical analysis showed there was no significant effect of del 3p on reduced β catenin staining for sites TBB (p=0.14), NBB (p=0.39), NTP (p=0.24), and TAB (p=0.24); however there was a significant correlation of del 3p from tumor touch preparations (TTP) on the percentage of cases with reduced staining (p=0.015).We did not observe any significant correlation of reduced staining when compared to stage of disease, histologic subtype, overall survival (OS) or recurrence-free survival (RS). There was also no significant correlation observed between Ki-67 proliferation index and β catenin expression or Ki-67 and OS/ RS. In conclusion, there is a significant correlation between del 3p22.1 and loss of β catenin staining in primary NSCLC, and reduced β catenin expression likely relates to tumor initiation and progression, secondary to dysregulated cell adhesion and EMT. (Funding: Specialized Program of Research Excellence grant P50CA70907) Citation Format: Sinchita Roy Chowdhuri, Tanweer M. Zaidi, Abha Khanna, Feng Jiang, Margaret R. Spitz, Ara A. Vaporciyan, Jack A. Roth, Joe Ensor, Ruth L. Katz. Deletion of 3p22.1 by FISH in non-small cell lung cancer (NSCLC) is significantly correlated with loss of β-catenin membrane expression and dysregulated cell adhesion. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 287. doi:10.1158/1538-7445.AM2013-287