title: CpG island methylator phenotype infers a poor disease-free survival in locally advanced rectal cancer.
abstract: BACKGROUND
  Locally advanced rectal cancers are treated with preoperative radiochemotherapy (RCT). However, subsets of patients have no benefit from preoperative treatment. Since epigenetic modifications, including DNA methylation, may influence response to neoadjuvant treatment we studied the CpG island methylator phenotype (CIMP) in patients who received a 5-fluouracil based RCT.
  
  
  METHODS
  One hundred fifty patients with locally advanced rectal cancer, treated within a phase III clinical trial (CAO/ARO/AIO-94 and -04), were included in this analysis. CIMP was assessed by methylation specific PCR (MSP) using RUNX3, SOCS1, NEUROG1, IGF2, and CACNA1G as a marker panel. Loss of mismatch repair gene (MMR) expression was assessed by immunohistochemistry for a subset of patients. KRAS and BRAF mutation status were assessed using Sanger sequencing.
  
  
  RESULTS
  The CIMP status could be established in all 150 patients. Fifteen (10%) revealed CIMP positivity (≥3 methylated promoters), whereas 135 patients (90%) where classified as CIMP negative. Analysis for MMR status did not reveal any microsatellite instability (MSI). A single mutation of the BRAF gene (D594G) was detected. The KRAS gene (exon 1, 2, and 3) was mutated in 65 tumors (43%) but was not correlated to a specific CIMP status. Three- and 5-year disease-free survival was notably worse in CIMP positive patients (56% and 0% vs 80% and 75%; P < .01) suggesting an increased likelihood of poor clinical outcome (HR 5.5; 95%CI: [2.1, 13.9]).
  
  
  CONCLUSIONS
  CIMP positivity, defined by methylation of at least 3 specific gene promoters, is an infrequent event in locally advanced rectal cancer. However, it increases the likelihood of distant metastases. Therefore, the CIMP status may be included as a molecular marker for the identification of high-risk patients and might contribute to individual treatment stratification.
authors: Department of General and Visceral Surgery, University Medicine Göttingen, Germany.
authors: Peter
authors: P
authors: Jo
authors: Klaus
authors: K
authors: Jung
authors: Marian
authors: M
authors: Grade
authors: Lena-Christin
authors: LC
authors: Conradi
authors: Hendrik A
authors: HA
authors: Wolff
authors: Julia
authors: J
authors: Kitz
authors: Heinz
authors: H
authors: Becker
authors: Josef
authors: J
authors: Rüschoff
authors: Arndt
authors: A
authors: Hartmann
authors: Tim
authors: T
authors: Beissbarth
authors: Annegret
authors: A
authors: Müller-Dornieden
authors: Michael
authors: M
authors: Ghadimi
authors: Regine
authors: R
authors: Schneider-Stock
authors: Jochen
authors: J
authors: Gaedcke
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor; D002277:Carcinoma / Q000175:diagnosis* / Q000628:therapy; D018899:CpG Islands; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012004:Rectal Neoplasms / Q000175:diagnosis* / Q000628:therapy
chemical_list: D014408:Biomarkers, Tumor