Moutinho, CátiaMartínez Cardús, AnnaSantos, CristinaNavarro-Pérez, ValentinMartínez Balibrea, EvaMusulén, EvaCarmona, F. JavierSartore-Bianchi, AndreaCassingena, AndreaSiena, SalvatoreÉlez, ElenaTabernero Caturla, JosepSalazar Soler, RamónAbad, AlbertEsteller, Manel2014-02-062013-11-220027-8874https://hdl.handle.net/2445/49478BACKGROUND: A major problem in cancer chemotherapy is the existence of primary resistance and/or the acquisition of secondary resistance. Many cellular defects contribute to chemoresistance, but epigenetic changes can also be a cause. METHODS: A DNA methylation microarray was used to identify epigenetic differences in oxaliplatin-sensitive and -resistant colorectal cancer cells. The candidate gene SRBC was validated by single-locus DNA methylation and expression techniques. Transfection and short hairpin experiments were used to assess oxaliplatin sensitivity. Progression-free survival (PFS) and overall survival (OS) in metastasic colorectal cancer patients were explored with Kaplan-Meier and Cox regression analyses. All statistical tests were two-sided. RESULTS: We found that oxaliplatin resistance in colorectal cancer cells depends on the DNA methylation-associated inactivation of the BRCA1 interactor SRBC gene. SRBC overexpression or depletion gives rise to sensitivity or resistance to oxaliplatin, respectively. SRBC epigenetic inactivation occurred in primary tumors from a discovery cohort of colorectal cancer patients (29.8%; n = 39 of 131), where it predicted shorter PFS (hazard ratio [HR] = 1.83; 95% confidence interval [CI] = 1.15 to 2.92; log-rank P = .01), particularly in oxaliplatin-treated case subjects for which metastasis surgery was not indicated (HR = 1.96; 95% CI = 1.13 to 3.40; log-rank P = .01). In a validation cohort of unresectable colorectal tumors treated with oxaliplatin (n = 58), SRBC hypermethylation was also associated with shorter PFS (HR = 1.90; 95% CI = 1.01 to 3.60; log-rank P = .045). CONCLUSIONS: These results provide a basis for future clinical studies to validate SRBC hypermethylation as a predictive marker for oxaliplatin resistance in colorectal cancer.9 p.application/pdfengcc-by-nc (c) Moutinho, Catia et al., 2013http://creativecommons.org/licenses/by-nc/3.0/es/EpigènesiCàncer colorectalGenètica mèdicaResistència als medicamentsEpigenesisColorectal cancerMedical geneticsDrug resistanceinfo:eu-repo/semantics/article6333082014-02-06info:eu-repo/semantics/openAccess24273214