Genetic and epigenetic classifications define clinical phenotypes and determine patient outcomes in colorectal cancer

Br J Surg. 2009 Oct;96(10):1196-204. doi: 10.1002/bjs.6683.


Background: A molecular classification of colorectal cancer has been proposed based on microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in the KRAS and BRAF oncogenes. This study examined the prevalence of these molecular classes, and differences in clinical presentation and outcome.

Methods: Demographics, tumour characteristics and survival were recorded for 391 subjects with colorectal cancer. Tumour DNA was analysed for MSI (high (MSI-H) or microsatellite stable (MSS)), CIMP (high (CIMP-H) or no (CIMP-neg)) and BRAF and KRAS mutations. Clinical differences between four phenotypes were examined.

Results: Most tumours were MSS/CIMP-neg (69.8 per cent), with a nearly equal distribution of MSI-H/CIMP-H, MSI-H/CIMP-neg and MSS/CIMP-H types. MSS/CIMP-neg tumours were less likely to be poorly differentiated (P = 0.009). CIMP-H tumours were more common in older patients (P < 0.001). MSI-H/CIMP-H tumours had a high frequency of BRAF mutation and a low rate of KRAS mutation; the opposite was true for MSS/CIMP-neg tumours (P < 0.001). The four molecular phenotypes tended towards divergent survival (P = 0.067 for stages 1-III). MSI-H cancers were associated with better disease-free survival (hazard ratio 2.00 (95 per cent confidence interval 1.03 to 3.91); P = 0.040).

Conclusion: Colorectal cancers are molecularly and clinically heterogeneous. These different molecular phenotypes may reflect variable prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Colorectal Neoplasms / classification
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / mortality
  • CpG Islands / genetics*
  • DNA Methylation / genetics*
  • Epigenesis, Genetic / genetics*
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Microsatellite Instability*
  • Middle Aged
  • Mutation / genetics
  • Oncogenes / genetics*
  • Phenotype
  • Proportional Hazards Models
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins / genetics


  • KRAS protein, human
  • Proto-Oncogene Proteins
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins