EZH2 expression is a prognostic biomarker in patients with colorectal cancer treated with anti-EGFR therapeutics

Itaru Yamamoto,Hiroyuki Okuda,Kenji Okita,Hideyuki Koide,Kei Mitsuhashi,Tadashi Hasegawa,Ichiro Takemasa,Hiroyuki Yamamoto,Yasutaka Sukawa,Hiroshi Nakase,Yasuhisa Shinomura,Kazuya Ishiguro,Hiroyoshi Kurihara,Shinichi Kanno,Reo Maruyama,Hisayoshi Igarashi,Katsuhiko Nosho,Keisuke Ishigami

doi:10.18632/oncotarget.14863

Abstract

The polycomb group protein enhancer of zeste homolog 2 (EZH2) is a methyltransferase that suppresses microRNA-31 (miR-31) in various human malignancies including colorectal cancer. We recently suggested that miR-31 regulates the signaling pathway downstream of epidermal growth factor receptor (EGFR) in colorectal cancer. Therefore, we conducted this study for assessing the relationship between EZH2 expression and clinical outcomes in patients with colorectal cancer treated with anti-EGFR therapeutics. We immunohistochemically evaluated EZH2 expression and assessed miR-31 and gene mutations [KRAS (codon 61/146), NRAS (codon 12/13/61), and BRAF (codon 600)] in 109 patients with colorectal cancer harboring KRAS (codon 12/13) wild-type. We also evaluated the progression-free survival (PFS) and overall survival (OS). In the result, low EZH2 expression was significantly associated with shorter PFS (log-rank test: P = 0.023) and OS (P = 0.036) in patients with colorectal cancer. In the low-miR-31-expression group and the KRAS (codon 61/146), NRAS, and BRAF wild-type groups, a significantly shorter PFS (P = 0.022, P = 0.039, P = 0.021, and P = 0.036, respectively) was observed in the EZH2 low-expression groups than in the high-expression groups. In the multivariate analysis, low EZH2 expression was associated with a shorter PFS (P = 0.046), independent of the mutational status and miR-31. In conclusion, EZH2 expression was associated with survival in patients with colorectal cancer who were treated with anti-EGFR therapeutics. Moreover, low EZH2 expression was independently associated with shorter PFS in patients with cancer, suggesting that EZH2 expression is a useful additional prognostic biomarker for anti-EGFR therapy.

Highlights

Monoclonal antibodies against the epidermal growth factor receptor (EGFR) have expanded the spectrum of therapeutic options; they have improved the clinical outcome of patients with metastatic colorectal cancer [1,2,3,4,5,6]
enhancer of zeste homolog 2 (EZH2) expression in 109 patients with colorectal cancer treated with anti-EGFR therapy
Of the 109 patients with colorectal cancer treated with anti-EGFR therapeutics, 50 (46%) received cetuximab and 59 (54%) received panitumumab

Summary

Introduction

Monoclonal antibodies against the epidermal growth factor receptor (EGFR) have expanded the spectrum of therapeutic options; they have improved the clinical outcome of patients with metastatic colorectal cancer [1,2,3,4,5,6]. The deregulation of the signaling pathways downstream of EGFR, including the RAS/RAF/MEK/ERK pathway, may induce resistance to anti-EGFR therapy. Regarding this resistance, a mutation in KRAS codon 61 or 146 has been actively studied as a possible additional predictive biomarker for anti-EGFR therapy [6, 7]. Regarding microRNA in the signaling pathway downstream of EGFR, we recently suggested that microRNA-31 (miR31)-5p regulates BRAF activation in colorectal cancer [23, 24] and that high miR-31-5p is associated with survival in patients with colorectal cancer who underwent surgical treatment and chemotherapy with anti-EGFR antibodies [19]

Methods

Results

Conclusion