Title:
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Epigenetic Inactivation of the BRCA1 Interactor SRBC and Resistance to Oxaliplatin in Colorectal Cancer
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Author:
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Moutinho, Cátia; Martínez Cardús, Anna; Santos, Cristina; Navarro-Pérez, Valentin; Martínez-Balibrea, Eva; Musulen, Eva; Carmona, F. Javier; Sartore-Bianchi, Andrea; Cassingena, Andrea; Siena, Salvatore; Élez, Elena; Tabernero Caturla, Josep; Salazar Soler, Ramón; Abad, Albert; Esteller, Manel
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Abstract:
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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. |
Subject(s):
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-Epigènesi -Càncer colorectal -Genètica mèdica -Resistència als medicaments -Epigenesis -Colorectal cancer -Medical genetics -Drug resistance |
Rights:
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cc-by-nc (c) Moutinho, Catia et al., 2013
http://creativecommons.org/licenses/by-nc/3.0/es/ |
Document type:
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Article Article - Published version |
Published by:
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Oxford University Press
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