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2013-11-22

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cc-by-nc (c) Moutinho, Catia et al., 2013
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/49478

Epigenetic Inactivation of the BRCA1 Interactor SRBC and Resistance to Oxaliplatin in Colorectal Cancer

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Recurs relacionat

http://dx.doi.org/10.1093/jnci/djt322

Resum

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.

Matèries

Epigènesi, Càncer colorectal, Genètica mèdica, Resistència als medicaments

Matèries (anglès)

Epigenesis, Colorectal cancer, Medical genetics, Drug resistance

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Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Citació

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. Epigenetic Inactivation of the BRCA1 Interactor SRBC and Resistance to Oxaliplatin in Colorectal Cancer. _Journal of the National Cancer Institute_. 2013. Vol. 106, núm. 1. [consulta: 20 de gener de 2026]. ISSN: 0027-8874. [Disponible a: https://hdl.handle.net/2445/49478]

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