title: IGFBP3 methylation is a novel diagnostic and predictive biomarker in colorectal cancer.
abstract: OBJECTIVE
  Aberrant hypermethylation of cancer-related genes has emerged as a promising strategy for the development of diagnostic, prognostic and predictive biomarkers in human cancer, including colorectal cancer (CRC). The aim of this study was to perform a systematic and comprehensive analysis of a panel of CRC-specific genes as potential diagnostic, prognostic and predictive biomarkers in a large, population-based CRC cohort.
  
  
  METHODS
  Methylation status of the SEPT9, TWIST1, IGFBP3, GAS7, ALX4 and miR137 genes was studied by quantitative bisulfite pyrosequencing in a population-based cohort of 425 CRC patients.
  
  
  RESULTS
  Methylation levels of all genes analyzed were significantly higher in tumor tissues compared to normal mucosa (p<0.0001); however, cancer-associated hypermethylation was most frequently observed for miR137 (86.7%) and IGFBP3 (83%) in CRC patients. Methylation analysis using the combination of these two genes demonstrated greatest accuracy for the identification of colonic tumors (sensitivity 95.5%; specificity 90.5%). Low levels of IGFBP3 promoter methylation emerged as an independent risk factor for predicting poor disease free survival in stage II and III CRC patients (HR = 0.49, 95% CI: 0.28-0.85, p = 0.01). Our results also suggest that stage II & III CRC patients with high levels of IGFBP3 methylation do not benefit from adjuvant 5FU-based chemotherapy.
  
  
  CONCLUSIONS
  By analyzing a large, population-based CRC cohort, we demonstrate the potential clinical significance of miR137 and IGFBP3 hypermethylation as promising diagnostic biomarkers in CRC. Our data also revealed that IGFBP3 hypermethylation may serve as an independent prognostic and predictive biomarker in stage II and III CRC patients.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Charles Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, United States of America.
authors.forename: Lucia
authors.initials: L
authors.lastname: Perez-Carbonell
authors.affiliation: Gastroenterology Department, Hospital Clinic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Balaguer
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Charles Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, United States of America.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Toiyama
authors.affiliation: Department of Pathology, Hospital General Universitario de Alicante, Alicante, Spain.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Egoavil
authors.affiliation: Department of Pathology, Hospital General Universitario de Alicante, Alicante, Spain.
authors.forename: Estefania
authors.initials: E
authors.lastname: Rojas
authors.affiliation: Research Unit, Hospital General Universitario de Alicante, Alicante, Spain.
authors.forename: Carla
authors.initials: C
authors.lastname: Guarinos
authors.affiliation: Gastroenterology Department, Hospital del Mar, Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Andreu
authors.affiliation: Department of Medicine and Cancer Center, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Xavier
authors.initials: X
authors.lastname: Llor
authors.affiliation: Gastroenterology Department, Hospital Clinic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Castells
authors.affiliation: Unidad de Gastroenterología, Hospital General Universitario de Alicante, Alicante, Spain.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Jover
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Charles Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, United States of America.
authors.forename: C Richard
authors.initials: CR
authors.lastname: Boland
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Charles Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, United States of America.
authors.forename: Ajay
authors.initials: A
authors.lastname: Goel
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D018972:Insulin-Like Growth Factor Binding Protein 3; D048493:Proto-Oncogene Proteins B-raf