We have recently shown that one allelic variant (rs3757441 CC versus TC/TT) of an EZH2 single nucleotide polymorphism (SNP) is significantly associated with shorter progression-free survival (PFS) and overall survival (OS) in metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI plus bevacizumab. EZH2 silences several tumor-suppressor genes, thereby enhancing cancer progression and chemoresistance. Recently, EZH2 has been shown to regulate tumor angiogenesis via a paracrine circuit promoted by the vascular endothelial growth factor (VEGF): VEGF increases endothelial EZH2 expression, thus promoting angiogenesis by methylating and silencing vasohibin1. In order to explore the value of the 626-394C>T SNP in predicting benefit of the anti-VEGF antibody bevacizumab, we genotyped a parallel group of 104 mCRC patients treated with first-line FOLFIRI without bevacizumab. Even though the small number of CC patients prevents any conclusive confirmation of our findings, these data suggest that the 626-394C>T SNP does not represent a potential predictive marker for bevacizumab efficacy but may play a role as either a prognostic variable or a predictive factor for first-line irinotecan-based chemotherapy in mCRC patients. The latter conclusion is supported also by the results of the Oncomine analysis reported elsewhere, which shows that EZH2 target genes are silenced in FOLFIRI nonresponders. Therefore, as stated in the conclusions of our article, the EZH2 626-394C>T SNP needs to be rigorously challenged in larger prospective independent series in order to definitively establish its value as a prognostic and/or predictive biomarker in mCRC.

EZH2 polymorphism and benefit from bevacizumab in colorectal cancer: another piece to the puzzle

MASI, GIANLUCA;PAOLICCHI, ELISA;CREMOLINI, CHIARA;DANESI, ROMANO;FALCONE, ALFREDO
2012

Abstract

We have recently shown that one allelic variant (rs3757441 CC versus TC/TT) of an EZH2 single nucleotide polymorphism (SNP) is significantly associated with shorter progression-free survival (PFS) and overall survival (OS) in metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI plus bevacizumab. EZH2 silences several tumor-suppressor genes, thereby enhancing cancer progression and chemoresistance. Recently, EZH2 has been shown to regulate tumor angiogenesis via a paracrine circuit promoted by the vascular endothelial growth factor (VEGF): VEGF increases endothelial EZH2 expression, thus promoting angiogenesis by methylating and silencing vasohibin1. In order to explore the value of the 626-394C>T SNP in predicting benefit of the anti-VEGF antibody bevacizumab, we genotyped a parallel group of 104 mCRC patients treated with first-line FOLFIRI without bevacizumab. Even though the small number of CC patients prevents any conclusive confirmation of our findings, these data suggest that the 626-394C>T SNP does not represent a potential predictive marker for bevacizumab efficacy but may play a role as either a prognostic variable or a predictive factor for first-line irinotecan-based chemotherapy in mCRC patients. The latter conclusion is supported also by the results of the Oncomine analysis reported elsewhere, which shows that EZH2 target genes are silenced in FOLFIRI nonresponders. Therefore, as stated in the conclusions of our article, the EZH2 626-394C>T SNP needs to be rigorously challenged in larger prospective independent series in order to definitively establish its value as a prognostic and/or predictive biomarker in mCRC.
Fornaro, L; Crea, F; Masi, Gianluca; Paolicchi, Elisa; Loupakis, F; Graziano, F; Salvatore, L; Ronzoni, M; Ricci, V; Cremolini, Chiara; Schirripa, M; Danesi, Romano; Falcone, Alfredo
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/199769
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