BackgroundA 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.MethodsA 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.ResultsWe 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).ConclusionsThese results provide a basis for future clinical studies to validate SRBC hypermethylation as a predictive marker for oxaliplatin resistance in colorectal cancer.
|Titolo:||Epigenetic inactivation of the BRCA1 interactor SRBC and resistance to oxaliplatin in colorectal cancer|
|Parole Chiave:||Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; Cell Line, Tumor; Chemotherapy, Adjuvant; Colorectal Neoplasms; CpG Islands; DNA Methylation; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; Kaplan-Meier Estimate; Male; Middle Aged; Organoplatinum Compounds; Proportional Hazards Models; RNA, Small Interfering; Transfection; Drug Resistance, Neoplasm; Gene Silencing; Cancer Research; Oncology|
|Settore Scientifico Disciplinare:||Settore MED/06 - Oncologia Medica|
|Data di pubblicazione:||gen-2014|
|Digital Object Identifier (DOI):||10.1093/jnci/djt322|
|Appare nelle tipologie:||01 - Articolo su periodico|