title: Identification of a quantitative MINT locus methylation profile predicting local regional recurrence of rectal cancer.
abstract: OBJECTIVE
  Risk assessment for locoregional disease recurrence would be highly valuable in preoperative treatment planning for patients undergoing primary rectal tumor resection. Epigenetic aberrations such as DNA methylation have been shown to be significant prognostic biomarkers of disease outcome. In this study, we evaluated the significance of a quantitative epigenetic multimarker panel analysis of primary tumors to predict local recurrence in rectal cancer patients from a retrospective multicenter clinical trial.
  
  
  METHODS
  Primary tumors were studied from patients enrolled in the trial who underwent total mesorectal excision for rectal cancer (n=325). Methylation levels of seven methylated-in-tumor (MINT) loci were assessed by absolute quantitative assessment of methylated alleles. Unsupervised random forest clustering of quantitative MINT methylation data was used to show subclassification into groups with matching methylation profiles.
  
  
  RESULTS
  Variable importance parameters [Gini-Index (GI)] of the clustering algorithm indicated MINT3 and MINT17 (GI, 20.2 and 20.7, respectively) to be informative for patient grouping compared with the other MINT loci (highest GI, 12.2). When using this two-biomarker panel, four different patient clusters were identified. One cluster containing 73% (184 of 251) of the patients was at significantly increased risk of local recurrence (hazard ratio, 10.23; 95% confidence interval, 1.38-75.91) in multivariate analysis, corrected for standard prognostic factors of rectal cancer. This group showed a significantly higher local recurrence probability than patients receiving preoperative radiation (P<0.0001).
  
  
  CONCLUSIONS
  Quantitative epigenetic subclassification of rectal cancers has clinical utility in distinguishing tumors with increased risk for local recurrence and may help tailor treatment regimens for locoregional control.
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California 90404, USA.
authors.forename: Michiel F G
authors.initials: MF
authors.lastname: de Maat
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: van de Velde
authors.forename: Anne
authors.initials: A
authors.lastname: Benard
authors.forename: Hein
authors.initials: H
authors.lastname: Putter
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.forename: J Han J M
authors.initials: JH
authors.lastname: van Krieken
authors.forename: Elma
authors.initials: E
authors.lastname: Meershoek Klein-Kranenbarg
authors.forename: Eelco J
authors.initials: EJ
authors.lastname: de Graaf
authors.forename: Rob A E M
authors.initials: RA
authors.lastname: Tollenaar
authors.forename: Dave S B
authors.initials: DS
authors.lastname: Hoon
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002986:Clinical Trials as Topic; D016000:Cluster Analysis; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D016601:RNA-Binding Proteins; D012004:Rectal Neoplasms / Q000235:genetics* / Q000473:pathology; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C476510:SPEN protein, human