EZH2 protein may aid prognostication in resected NSCLC

By Joanna Lyford, Senior medwireNews Reporter

A protein called “enhancer of zeste homolog-2” (EZH2) is frequently expressed in non-small-cell lung cancer (NSCLC) and may have prognostic value following surgical resection, US researchers believe.

EZH2 is a key component of the polycomb repressive complex-2 and is known to promote carcinogenesis through epigenetic activation of oncogenic signaling cascades and silencing of tumor suppressor genes.

In this study, Carmen Behrens (The University of Texas MD Anderson Cancer Center, Houston) and team used immunohistochemistry (IHC) to measure EZH2 expression in a series of 541 surgically resected primary NSCLCs and 36 NSCLCs with paired brain metastases.

Writing in Clinical Cancer Research, the authors report that EZH2 expression was significantly higher in squamous cell carcinomas than adenocarcinomas (mean IHC score 124.9 vs 56.6) and significantly higher in brain metastases than matched primary tumors (mean 109.8 vs 75.1).

EZH2 expression was also increased in bronchial neoplastic lesions, with levels rising in line with the severity of the lesion. Mean levels were 2.0 in normal epithelia, 11.0 in hyperplastic lesions, 35.2 in squamous metaplasia, 57.8 in low-grade dysplasia, and 95.9 in high-grade dysplasia.

In adenocarcinomas but not squamous cell carcinomas, EZH2 expression correlated with multiple clinicopathologic variables, such as age, smoking status, tumor size, tumor stage, and proportion of solid component.

Multivariate analysis confirmed that EZH2 expression in adenocarcinomas was significantly associated with overall survival and recurrence-free survival, with hazard ratios (HRs) of 1.94 and 1.83, respectively, for patients with above-median versus below-median scores (median=41.7).

The team then measured levels of another prognostic marker, the lineage-specific transcription factor TTF-1. They found that TTF-1 expression was higher in tumors from women, in smaller tumors, and in lower-stage tumors.

After multivariate adjustment, TTF-1 expression was significantly associated with overall survival and recurrence-free survival, with HRs of 0.62 and 0.67 for patients with below-median versus above-median scores (median=150).

Finally, Behrens et al combined EZH2 and TTF-1 expression into a predictive model and found that both markers were better able than either marker alone to predict clinical outcomes in patients with resected adenocarcinomas, with a C-index of 0.70 for recurrence-free survival and 0.69 for overall survival.

The researchers conclude: “[O]ur findings indicate that high expression of EZH2 predicts for aggressive tumor behavior correlates with more rapid progression of preneoplastic lesions to an invasive malignancy and development of metastasis.

“Importantly, EZH2 expression, particularly when combined with TTF-1 expression, allows us to more accurately predict the true prognosis of definitely treated adenocarcinomas of the lung.”

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