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dc.contributor | Universitat de Barcelona |
---|---|
dc.contributor.author | Moutinho, Cátia |
dc.contributor.author | Martínez Cardús, Anna |
dc.contributor.author | Santos, Cristina |
dc.contributor.author | Navarro-Pérez, Valentin |
dc.contributor.author | Martínez-Balibrea, Eva |
dc.contributor.author | Musulen, Eva |
dc.contributor.author | Carmona, F. Javier |
dc.contributor.author | Sartore-Bianchi, Andrea |
dc.contributor.author | Cassingena, Andrea |
dc.contributor.author | Siena, Salvatore |
dc.contributor.author | Élez, Elena |
dc.contributor.author | Tabernero Caturla, Josep |
dc.contributor.author | Salazar Soler, Ramón |
dc.contributor.author | Abad, Albert |
dc.contributor.author | Esteller, Manel |
dc.date | 2014-02-06T13:56:06Z |
dc.date | 2013-11-22 |
dc.date | 2014-02-06T09:44:19Z |
dc.identifier.citation | 0027-8874 |
dc.identifier.citation | 633308 |
dc.identifier.uri | http://hdl.handle.net/2445/49478 |
dc.description.abstract | 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. |
dc.format | 9 p. |
dc.format | application/pdf |
dc.language.iso | eng |
dc.publisher | Oxford University Press |
dc.relation | Reproducció del document publicat a: http://dx.doi.org/10.1093/jnci/djt322 |
dc.relation | Journal of the National Cancer Institute, 2013, vol. 106, num. 1 |
dc.relation | http://dx.doi.org/10.1093/jnci/djt322 |
dc.rights | cc-by-nc (c) Moutinho, Catia et al., 2013 |
dc.rights | info:eu-repo/semantics/openAccess |
dc.rights | http://creativecommons.org/licenses/by-nc/3.0/es/ |
dc.subject | Epigènesi |
dc.subject | Càncer colorectal |
dc.subject | Genètica mèdica |
dc.subject | Resistència als medicaments |
dc.subject | Epigenesis |
dc.subject | Colorectal cancer |
dc.subject | Medical genetics |
dc.subject | Drug resistance |
dc.title | Epigenetic Inactivation of the BRCA1 Interactor SRBC and Resistance to Oxaliplatin in Colorectal Cancer |
dc.type | info:eu-repo/semantics/article |
dc.type | info:eu-repo/semantics/publishedVersion |