The impact of CpG island methylator phenotype and microsatellite instability on tumour budding in colorectal cancer

Histopathology. 2012 Nov;61(5):777-87. doi: 10.1111/j.1365-2559.2012.04273.x. Epub 2012 Jul 16.


Aims: In colorectal cancer, tumour budding, a process likened to epithelial mesenchymal transition, is an adverse prognostic factor which is rarely found in tumours with high-level microsatellite instability (MSI-H). Cases with MSI-H or high-level CpG island methylator phenotype (CIMP-H) have similar histomorphological features, yet seemingly opposite prognosis. We hypothesized that tumour budding is related to CIMP, thus partially explaining this prognostic difference.

Methods and results: MSI, KRAS, BRAF, CIMP and 0(6)-methylguanine-DNA methyltransferase (MGMT) were investigated in tissues from 127 colorectal cancer patients. Tumour budding was scored using pan-cytokeratin-stained whole tissue sections within the densest area of buds (×40). Tumour budding was not associated with KRAS, BRAF, MGMT or CIMP, but was correlated inversely with MSI-H (P = 0.0049). Multivariate survival time analysis revealed that tumour budding was independent of all five molecular features and was predicted by MSI status [odds ratio (OR): 4.29, 95% confidence interval (CI) 1.5-12.1; P = 0.006)], but not CIMP (OR: 0.81, 95% CI 0.3-2.5; P = 0.714).

Conclusions: These findings underline that MSI, rather than CIMP, plays a role in conferring a tumour budding phenotype. Budding retains its unfavourable prognostic effect independently of these five molecular features. Continued efforts to standardize the assessment of tumour budding are necessary to integrate this feature into daily diagnostic routine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Adenocarcinoma, Mucinous / genetics
  • Adenocarcinoma, Mucinous / pathology
  • Adult
  • Aged
  • Aged, 80 and over
  • Base Sequence
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology*
  • CpG Islands*
  • DNA Methylation
  • DNA Modification Methylases / genetics
  • DNA Repair Enzymes / genetics
  • DNA, Neoplasm / genetics*
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Genes, Tumor Suppressor
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Microsatellite Instability*
  • Middle Aged
  • Phenotype
  • Prognosis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins p21(ras)
  • Tumor Suppressor Proteins / genetics
  • ras Proteins / genetics


  • DNA, Neoplasm
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins
  • DNA Modification Methylases
  • MGMT protein, human
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • DNA Repair Enzymes