title: Epigenetic inactivation of the BRCA1 interactor SRBC and resistance to oxaliplatin in colorectal cancer.
abstract: 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.
authors.affiliation: 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); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (ME).
authors.forename: Catia
authors.initials: C
authors.lastname: Moutinho
authors.forename: Anna
authors.initials: A
authors.lastname: Martinez-Cardús
authors.forename: Cristina
authors.initials: C
authors.lastname: Santos
authors.forename: Valentin
authors.initials: V
authors.lastname: Navarro-Pérez
authors.forename: Eva
authors.initials: E
authors.lastname: Martínez-Balibrea
authors.forename: Eva
authors.initials: E
authors.lastname: Musulen
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Carmona
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.forename: Andrea
authors.initials: A
authors.lastname: Cassingena
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
authors.forename: Elena
authors.initials: E
authors.lastname: Elez
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Ramon
authors.initials: R
authors.lastname: Salazar
authors.forename: Albert
authors.initials: A
authors.lastname: Abad
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics*; D000069287:Capecitabine; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000601:surgery; D018899:CpG Islands; D019175:DNA Methylation; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin; D016016:Proportional Hazards Models; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C505360:CAVIN3 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009944:Organoplatinum Compounds; D034741:RNA, Small Interfering; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil