title: Divergent oncogenic changes influence survival differences between colon and rectal adenocarcinomas.
abstract: OBJECTIVE
  Colorectal cancers develop through various mechanisms such as chromosomal instability, DNA mismatch repair deficiency (microsatellite instability), and epigenetic DNA promoter methylation (CpG island methylator phenotype). This study evaluated the disparity in neoplastic changes between colon and rectal cancers.
  
  
  METHODS
  A clinic-based colorectal frozen tumor bank at a single institution was queried for colon and rectal adenocarcinomas. Tumor DNA was extracted and analyzed for microsatellite instability, methylation, and mutations in the oncogenes KRAS and BRAF. Patient demographics, tumor characteristics, and clinical outcomes were compared.
  
  
  RESULTS
  The 268 patients with colon cancer and 89 with rectal cancer were similar in gender, tumor size, stage, and differentiation. Colon cancers had a higher incidence of microsatellite instability (27 percent) and methylator phenotype (28 percent) compared with rectal cancers (7 percent, 3 percent, respectively; P < 0.001). Although KRAS mutation rate was similar, colon cancers had a higher incidence of BRAF mutations (16.7 percent vs. 0 percent; P < 0.001). Microsatellite stable tumors had an increased risk of disease recurrence compared with microsatellite unstable tumors (odds ratio, 3.86). Despite overall differences in outcome between colon and rectal cancers, no significant difference in survival existed when similar molecular phenotypes were compared across anatomic sites.
  
  
  CONCLUSIONS
  Although colon cancers are molecularly heterogeneous, rectal cancers arise mostly via a single neoplastic pathway. Genetic and molecular differences influence prognosis more than anatomic location and suggest that oncogenic pathways contribute to survival differences between colon and rectal cancers.
authors: Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio, USA. kaladym@ccf.org
authors: Matthew F
authors: MF
authors: Kalady
authors: Julian A
authors: JA
authors: Sanchez
authors: Elena
authors: E
authors: Manilich
authors: Jeff
authors: J
authors: Hammel
authors: Graham
authors: G
authors: Casey
authors: James M
authors: JM
authors: Church
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000328:Adult; D016009:Chi-Square Distribution; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D018899:CpG Islands; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009367:Neoplasm Staging; D010641:Phenotype; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012004:Rectal Neoplasms / Q000235:genetics / Q000473:pathology*; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D018631:ras Proteins / Q000235:genetics
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins