title: CHFR promoter methylation indicates poor prognosis in stage II microsatellite stable colorectal cancer.
abstract: OBJECTIVE
  Data on the prognostic significance of promoter CpG island methylation in colorectal cancer (CRC) are conflicting, possibly due to associations between methylation and other factors affecting survival such as genetic alterations and use of adjuvant therapy. Here, we examine the prognostic impact of promoter methylation in patients with CRC treated with surgery alone in the context of microsatellite instability (MSI), BRAF and KRAS mutations.
  
  
  METHODS
  One hundred and seventy-three CRCs were analyzed for promoter methylation of 19 tumor suppressor and DNA repair genes, the CpG island methylator phenotype (CIMP), MSI, the exon 15 V600E BRAF mutation and KRAS codon 12 and 13 mutations.
  
  
  RESULTS
  Unsupervised hierarchical clustering based on methylation status of 19 genes revealed three subgroups: cluster 1 [CL1, 57% (98/173) of CRCs], cluster 2 [CL2, 25% (43/173) of CRCs], and cluster 3 [CL3, 18% (32/173) of CRCs]. CL3 had the highest methylation index (0.25, 0.49, and 0.69, respectively, P = <0.01) and was strongly associated with CIMP (P < 0.01). Subgroup analysis for tumor stage, MSI, and BRAF status showed no statistically significant differences in survival between CL1, CL2, and CL3 nor between CIMP and non-CIMP CRCs. Analyzing genes separately revealed that CHFR promoter methylation was associated with a poor prognosis in stage II, microsatellite stability (MSS), BRAF wild-type (WT) CRCs: multivariate Cox proportional HR = 3.89 [95% confidence interval (CI), 1.58-9.60, P < 0.01; n = 66] and HR = 2.11 (95% CI, 0.95-4.69, P = 0.068, n = 136) in a second independent population-based study.
  
  
  CONCLUSIONS
  CHFR promoter CpG island methylation, which is associated with MSI, also occurs frequently in MSS CRCs and is a promising prognostic marker in stage II, MSS, BRAF WT CRCs.
authors.affiliation: Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Arjen H G
authors.initials: AH
authors.lastname: Cleven
authors.affiliation: Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Derks
authors.affiliation: Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Muriel X G
authors.initials: MX
authors.lastname: Draht
authors.affiliation: Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, MarylandAuthors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Smits
authors.affiliation: Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Veerle
authors.initials: V
authors.lastname: Melotte
authors.affiliation: Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Leander
authors.initials: L
authors.lastname: Van Neste
authors.affiliation: Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Tournier
authors.affiliation: Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Valerie
authors.initials: V
authors.lastname: Jooste
authors.affiliation: Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Chapusot
authors.affiliation: Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Matty P
authors.initials: MP
authors.lastname: Weijenberg
authors.affiliation: Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.affiliation: Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: de Bruïne
authors.affiliation: Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland manon.van.engeland@mumc.nl.
authors.forename: Manon
authors.initials: M
authors.lastname: van Engeland
mesh_terms: D000368:Aged; D018797:Cell Cycle Proteins / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D010641:Phenotype; D000075223:Poly-ADP-Ribose Binding Proteins; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011446:Prospective Studies; D015996:Survival Rate; D044767:Ubiquitin-Protein Ligases
chemical_list: D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases