• Cancer stem cell
• Colorectal cancer
• EZH2
• FOLFIRI
• Polycomb
• Single nucleotide polymorphisms
• Bevacizumab

Despite therapeutic innovations, metastatic colorectal cancer (mCRC) is still characterized by poor prognosis. Few molecular markers are available to predict progression risk and to help therapeutic decisions. Polycomb group genes (PcGs) are epigenetic modifiers involved in tumor suppressor gene silencing. EZH2 is a PcG member, that mediates gene silencing through histone-H3 lysine-27 methylation. In CRC, EZH2 over-expression is associated to shorter survival. Recently, 4 EZH2 single nucleotide polymorphisms (SNPs) have been characterized: the present study aimed at evaluating the correlation between EZH2 SNPs and outcome parameters in mCRC patients.
DNA was extracted from blood samples of 110 mCRC patients treated with first-line FOLFIRI plus bevacizumab, and 104 mCRC patients treated with FOLFIRI. Genotyping was performed by Real-Time PCR. Allelic variant distribution was used to predict objective response, progression-free survival (PFS) and overall survival (OS). EZH2 mRNA levels were evaluated on lymphocytes of a parallel cohort of 50 radically resected stage II or III CRC patients.
One allelic variant (rs3757441 C/C vs. C/T or T/T) was significantly associated to shorter PFS and OS in both mCRC patients cohorts receiving first-line FOLFIRI (with or without bevacizumab). At multivariate analysis, the same variant resulted an independent predictor of both PFS and OS (p<0.05). Among the 50 patients analysed for EZH2 expression and genotyped for EZH2 rs3757441 SNP, mRNA levels were significantly higher in patients harbouring the C/C genotype with respect to C/T and T/T (p<0.05), with no difference between C/T and T/T genotypes.
Our results indicate that an EZH2 SNP may be useful to predict PFS and OS in mCRC patients treated with first-line FOLFIRI (with or without bevacizumab).