Background: Experimental and clinical evidence supports a role for the circadian timing system in cancer. Gender and delivery schedule (chronomodulated or conventional) influence overall survival (OS) in mCRC pts (Giacchetti 2014). Circadian rhythms are generated by a transcription-translation–based oscillatory loop and involve a set of clock genes including PERIOD, CLOCK, BMAL1, CRY. Here we evaluated the expression of CLOCK gene-related miRNAs and SNPs in mCRC pts and their effect according to gender Methods: We studied 83 first line mCRC pts treated with chemotherapy plus cetuximab. Specific CLOCK polymorphisms (SNPs) (rs11133373C/G, rs11133391T/C, rs1801260T/C) and miRNAs expression level (miR-192-206-132-194-219) were performed on formalin fixed paraffin embedded tissues in 77 pts. OS was the primary study endpoint. Results: Median age 59 y (30-85); male/female (M/F) 50/33; median follow-up 25 m (1-132); median PFS was 14 m (CI 95% 10-19) and median OS was 35 m (CI 95% 22-47). PFS and OS were significantly better in F: PFS M/F = 12/19 m (CI 95% 8-16/11-27) p = 0.03; OS M/F = 31/50 m (CI 95% 22-39/35-64) p = 0.03. Increased OS in F vs M was related to high expression level (H) of miR206 (p = 0.003), miR219 (p = 0.003) and miR194 (p = 0.02), and low expression (L) of miR132 (p = 0.06). OS was also better in F vs M in the presence of genotype RS11133373C/C (p = 0.01), RS1801260T/T (p = 0.07) and RS11133391T/T (p = 0.06). Subgroup analysis in females showed that OS was significantly better when ≥ 2 beneficial miRNA were simultaneously expressed vs 0/1 (58 m vs 15 m, p = 0.0002) and this effect was additionally increased by the presence of RS11133391T/T polymorphism (median OS 87 m). Although no difference in OS was observed between M and F respect to L of miR206 and H of miR132, OS was significantly decreased in F when L of miR206 and H of miR132 were simultaneously expressed vs 0/1 (11 m vs 56 m, p = 0.02). No difference in OS was observed in subgroup analysis in males Conclusions: A set of SNPs and miRNAs related to CLOCK gene, principal regulator of the molecular clock, identifies a subgroup of pts who benefits of a gender related difference in survival in mCRC. Supported by AIRC11770

Effect of polymorphisms and miRNAs targeting CLOCK gene on gender-related survival in metastatic colorectal cancer (mCRC) patients (pts).

RUZZO, ANNAMARIA;GIACOMINI, ELISA;MAGNANI, MAURO;
2015-01-01

Abstract

Background: Experimental and clinical evidence supports a role for the circadian timing system in cancer. Gender and delivery schedule (chronomodulated or conventional) influence overall survival (OS) in mCRC pts (Giacchetti 2014). Circadian rhythms are generated by a transcription-translation–based oscillatory loop and involve a set of clock genes including PERIOD, CLOCK, BMAL1, CRY. Here we evaluated the expression of CLOCK gene-related miRNAs and SNPs in mCRC pts and their effect according to gender Methods: We studied 83 first line mCRC pts treated with chemotherapy plus cetuximab. Specific CLOCK polymorphisms (SNPs) (rs11133373C/G, rs11133391T/C, rs1801260T/C) and miRNAs expression level (miR-192-206-132-194-219) were performed on formalin fixed paraffin embedded tissues in 77 pts. OS was the primary study endpoint. Results: Median age 59 y (30-85); male/female (M/F) 50/33; median follow-up 25 m (1-132); median PFS was 14 m (CI 95% 10-19) and median OS was 35 m (CI 95% 22-47). PFS and OS were significantly better in F: PFS M/F = 12/19 m (CI 95% 8-16/11-27) p = 0.03; OS M/F = 31/50 m (CI 95% 22-39/35-64) p = 0.03. Increased OS in F vs M was related to high expression level (H) of miR206 (p = 0.003), miR219 (p = 0.003) and miR194 (p = 0.02), and low expression (L) of miR132 (p = 0.06). OS was also better in F vs M in the presence of genotype RS11133373C/C (p = 0.01), RS1801260T/T (p = 0.07) and RS11133391T/T (p = 0.06). Subgroup analysis in females showed that OS was significantly better when ≥ 2 beneficial miRNA were simultaneously expressed vs 0/1 (58 m vs 15 m, p = 0.0002) and this effect was additionally increased by the presence of RS11133391T/T polymorphism (median OS 87 m). Although no difference in OS was observed between M and F respect to L of miR206 and H of miR132, OS was significantly decreased in F when L of miR206 and H of miR132 were simultaneously expressed vs 0/1 (11 m vs 56 m, p = 0.02). No difference in OS was observed in subgroup analysis in males Conclusions: A set of SNPs and miRNAs related to CLOCK gene, principal regulator of the molecular clock, identifies a subgroup of pts who benefits of a gender related difference in survival in mCRC. Supported by AIRC11770
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11576/2628181
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