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

• Published in: JNCI : Journal of the National Cancer Institute Vol. 106; no. 1; p. djt322
• Main Authors: Moutinho, Catia, Martinez-Cardús, Anna, Santos, Cristina, Navarro-Pérez, Valentin, Martínez-Balibrea, Eva, Musulen, Eva, Carmona, F. Javier, Sartore-Bianchi, Andrea, Cassingena, Andrea, Siena, Salvatore, Elez, Elena, Tabernero, Josep, Salazar, Ramon, Abad, Albert, Esteller, Manel
• Format: Journal Article
• Language: English
• Published: Cary, NC Oxford University Press 01.01.2014; Oxford Publishing Limited (England)
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; BRCA1 Protein - genetics; Capecitabine; Cell Line, Tumor; Chemotherapy; Chemotherapy, Adjuvant; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - surgery; CpG Islands; Càncer colorectal; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Disease-Free Survival; DNA Methylation; Drug resistance; Drug Resistance, Neoplasm; Epigenesis; Epigenetics; Epigènesi; Female; Fluorouracil - administration & dosage; Fluorouracil - analogs & derivatives; Gastroenterology. Liver. Pancreas. Abdomen; Gene expression; Gene Expression Regulation, Neoplastic; Gene Silencing; Genètica mèdica; Humans; Intracellular Signaling Peptides and Proteins - genetics; Kaplan-Meier Estimate; Male; Medical genetics; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Organoplatinum Compounds - therapeutic use; Oxaliplatin; Proportional Hazards Models; Resistència als medicaments; RNA, Small Interfering - genetics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Survival analysis; Transfection; Tumors; Antineoplastic agent; Rectal disease; Colorectal cancer; Malignant tumor; Inactivation; Colonic disease; Resistance; Alkylating agent; Cancerology; Oxaliplatin; Epigenetics; Digestive diseases; Intestinal disease; BRCA1 gene; Cancer; Platinum II Complexes; Tumor suppressor gene
• ISSN: 0027-8874; 1460-2105; 1460-2105
• DOI: 10.1093/jnci/djt322

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. 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. 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). These results provide a basis for future clinical studies to validate SRBC hypermethylation as a predictive marker for oxaliplatin resistance in colorectal cancer.