Multiregional assessment of CIMP in primary colorectal cancers: Phenotype concordance but marker variability

Int J Cancer. 2021 Apr 1;148(7):1652-1657. doi: 10.1002/ijc.33425. Epub 2020 Dec 16.


Intratumor heterogeneity of colorectal cancers (CRCs) is manifested both at the genomic and epigenomic levels. Early genetic aberrations in carcinogenesis are clonal and present throughout the tumors, but less is known about the heterogeneity of the epigenetic CpG island methylator phenotype (CIMP). CIMP characterizes a subgroup of CRCs thought to originate from specific precursor lesions, and it is defined by widespread DNA methylation within promoter regions. In this work, we investigated CIMP in two to four multiregional samples from 30 primary tumors (n = 86 samples) using the consensus Weisenberger gene panel (CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1). Twenty-nine of 30 tumors (97%) showed concordant CIMP status in all samples, and percent methylated reference (PMR) values of all five markers had higher intertumor than intratumor variation (P value = 1.5e-09). However, a third of the CIMP+ tumors exhibited discrepancies in methylation status in at least one of the five gene markers. To conclude, CIMP status was consistent within primary CRCs, and it is likely a clonal phenotype. However, spatial discordances of the individual genes suggest that large-scale analysis of multiregional samples could be of interest for identifying CIMP markers that are robust to intratumor heterogeneity.

Keywords: CpG island methylator phenotype (CIMP); Weisenberger panel; colorectal cancer; multiregional sampling; spatial intratumor heterogeneity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Calcium Channels, T-Type / genetics
  • Calcium Channels, T-Type / metabolism
  • Colorectal Neoplasms / pathology
  • Core Binding Factor Alpha 3 Subunit / genetics
  • Core Binding Factor Alpha 3 Subunit / metabolism
  • CpG Islands / genetics*
  • DNA Methylation*
  • Female
  • Humans
  • Insulin-Like Growth Factor II / genetics
  • Insulin-Like Growth Factor II / metabolism
  • Male
  • Microsatellite Instability
  • Middle Aged
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Suppressor of Cytokine Signaling 1 Protein / genetics
  • Suppressor of Cytokine Signaling 1 Protein / metabolism


  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers, Tumor
  • CACNA1G protein, human
  • Calcium Channels, T-Type
  • Core Binding Factor Alpha 3 Subunit
  • IGF2 protein, human
  • NEUROG1 protein, human
  • Nerve Tissue Proteins
  • Runx3 protein, human
  • SOCS1 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • Insulin-Like Growth Factor II