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oai:recercat.cat:2445/494782025-12-05T09:21:07Zcom_2072_1057col_2072_478799col_2072_478916col_2072_478917

Epigenetic Inactivation of the BRCA1 Interactor SRBC and Resistance to Oxaliplatin in Colorectal Cancer Moutinho, Cátia Martínez Cardús, Anna Santos, Cristina Navarro-Pérez, Valentin Martínez Balibrea, Eva Musulén, Eva Carmona, F. Javier Sartore-Bianchi, Andrea Cassingena, Andrea Siena, Salvatore Élez, Elena Tabernero Caturla, Josep Salazar Soler, Ramón Abad, Albert Esteller, Manel Epigènesi Càncer colorectal Genètica mèdica Resistència als medicaments Epigenesis Colorectal cancer Medical genetics Drug resistance BACKGROUND: 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. 2014-02-06T13:56:06Z 2013-11-22 2014-02-06T09:44:19Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 0027-8874 https://hdl.handle.net/2445/49478 633308 24273214 eng Reproducció del document publicat a: http://dx.doi.org/10.1093/jnci/djt322 Journal of the National Cancer Institute, 2013, vol. 106, num. 1 http://dx.doi.org/10.1093/jnci/djt322 info:eu-repo/grantAgreement/EC/FP7/259015/EU//COLTHERES cc-by-nc (c) Moutinho, Catia et al., 2013 http://creativecommons.org/licenses/by-nc/3.0/es/ info:eu-repo/semantics/openAccess 9 p. application/pdf Oxford University Press Articles publicats en revistes (Ciències Fisiològiques)