Medline ® Abstract for Reference 95
of 'Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations'
Epigenetic inactivation of the BRCA1 interactor SRBC and resistance to oxaliplatin in colorectal cancer.
Moutinho C, Martinez-Cardús A, Santos C, Navarro-Pérez V, Martínez-Balibrea E, Musulen E, Carmona FJ, Sartore-Bianchi A, Cassingena A, Siena S, Elez E, Tabernero J, Salazar R, Abad A, Esteller M
J Natl Cancer Inst. 2014 Jan;106(1):djt322. Epub 2013 Nov 22.
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.
Affiliations of authors: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, Barcelona, Spain (CM, AM-C, FJC, ME); Medical Oncology Service, Catalan Institute of Oncology, Health Sciences Research Institute of the Germans Trias i Pujol Foundation, Barcelona, Spain (AM-C, EM-B, AA); Department of Medical Oncology (CS, RS) and Clinical Informatics Unit (VN-P), Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain; Department of Pathology, Germans Trias i Pujol Foundation, Barcelona, Spain (EM); Department of Hematology and Oncology, Ospedale Niguarda Ca' Granda, Milan, Italy (AS-B, AC, SS); Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain (EE, JT); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Barcelona, Spain (ME); InstitucióCatalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (ME).