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

// Itaru Yamamoto 1, * , Katsuhiko Nosho 1, * , Shinichi Kanno 1, * , Hisayoshi Igarashi 1, * , Hiroyoshi Kurihara 1 , Keisuke Ishigami 1 , Kazuya Ishiguro 1 , Kei Mitsuhashi 1 , Reo Maruyama 2 , Hideyuki Koide 1 , Hiroyuki Okuda 3 , Tadashi Hasegawa 4 , Yasutaka Sukawa 1 , Kenji Okita 5 , Ichiro Takemasa 5 , Hiroyuki Yamamoto 6 , Yasuhisa Shinomura 7 , Hiroshi Nakase 1 1 Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan 2 Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan 3 Department of Oncology, Keiyukai Sapporo Hospital, Sapporo, Japan 4 Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan 5 Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan 6 Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan 7 Department of Gastroenterology, Ikeda Municipal Hospital, Ikeda, Japan * These authors contributed equally to this work Correspondence to: Katsuhiko Nosho, email: nosho@sapmed.ac.jp Keywords: EZH2, microRNA-31, colon cancer, EGFR, CIMP Received: September 16, 2016      Accepted: January 16, 2017      Published: January 27, 2017 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.