Abstract 3196: EZH2 expression is an early event in the pathogenesis of non-small cell lung cancer (NSCLC) and correlates with tumor progression

Abstract

Abstract Background. The molecular events associated with NSCLC pathogenesis and tumor progression need to be better elucidated. The enhancer of zeste homolog 2 (EZH2) is a DNA methyl transferase involved in malignant transformation and tumor progression of several human carcinomas, including lung. We investigated EZH2 expression by immunohistochemistry (IHC) in the early pathogenesis of NSCLC and progression in a large series of clinically well-annotated tissue specimens. Methods. We examined by IHC nuclear EZH2 expression using formalin-fixed and paraffin-embedded tissue specimens obtained from surgically resected tumors in tissue microarrays (TMAs) including: a) stage I-III NSCLC tumors (SCCs, n=272; adenocarcinomas, n=456); b) paired primary tumors and brain metastases (n=70); and, c) bronchial preneoplastic squamous lesions (n=51) and mildly abnormal/normal bronchial epithelia (n=203). In stage I-III tumors, we correlated EZH2 expression with clinico-pathological features, including patients’ recurrence-free survival (RFS), and overall survival (OS), in a subset of these tumors, with IHC expression of 80 proteins and EGFR and KRAS mutation status. Results. EZH2 expression was significantly (P<0.0001) higher in SCC (mean score=128.6) compared to adenocarcinoma (mean score=56.8). In adenocarcinoma, higher EZH2 expression significantly correlated with ever-smoking status (P<0.0001) and less differentiated histology features (solid histology pattern; P<0.0001). In multivariate analysis, for adenocarcinoma patients, higher EZH2 expression, as a continuous variable, associated with significantly worse RFS (HR 1.006 95%CI 1.0-1.011; P=0.03) and OS (HR 1.004 95%CI 1.0-1.009; P=0.03). In publicly available array datasets of lung adenocarcinoma patients, high EZH2 mRNA correlated with worse RFS and OS. NSCLC brain metastases showed significantly (P=0.0004) higher EZH2 expression than corresponding primary tumors. In bronchial epithelia, normal and hyperplastic cells demonstrated low levels of EZH2 expression; significantly higher expression was associated with increasing severity of squamous dysplastic changes (P<0.0001). In NSCLC tumors, EZH2 expression positively correlated (P<0.0001) with IHC expression of Ki67, FEN1, and UBE2C. In lung adenocarcinomas, EGFR-mutant tumors showed significantly lower EZH2 expression than wild-type tumors. Conclusions. Our findings indicate that EZH2 is frequently expressed in NSCLC, particularly in poorly differentiated adenocarcinomas. In adenocarcinomas, EZH2 associates with worse patient outcomes. These data suggest that EZH2 expression represents an early event in NSCLC pathogenesis and associates with tumor progression and metastasis, representing a novel target for chemoprevention and therapeutic strategies. Supported by DoD grants W81XWH-04-1-0142 and DoD W81XWH-07-1-0306. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3196. doi:10.1158/1538-7445.AM2011-3196