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Title: | Epigenetic Inactivation of the BRCA1 Interactor SRBC and Resistance to Oxaliplatin in Colorectal Cancer |
Author: | 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 |
Keywords: | Epigènesi Càncer colorectal Genètica mèdica Resistència als medicaments Epigenesis Colorectal cancer Medical genetics Drug resistance |
Issue Date: | 22-Nov-2013 |
Publisher: | Oxford University Press |
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. |
Note: | Reproducció del document publicat a: http://dx.doi.org/10.1093/jnci/djt322 |
It is part of: | Journal of the National Cancer Institute, 2013, vol. 106, num. 1 |
URI: | http://hdl.handle.net/2445/49478 |
Related resource: | http://dx.doi.org/10.1093/jnci/djt322 |
ISSN: | 0027-8874 |
Appears in Collections: | Articles publicats en revistes (Ciències Fisiològiques) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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