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The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer.

Publication ,  Journal Article
Goel, A; Nagasaka, T; Arnold, CN; Inoue, T; Hamilton, C; Niedzwiecki, D; Compton, C; Mayer, RJ; Goldberg, R; Bertagnolli, MM; Boland, CR
Published in: Gastroenterology
January 2007

BACKGROUND & AIMS: The CpG island methylator phenotype (CIMP) is one of the mechanisms involved in colorectal carcinogenesis (CRC). Although CIMP is probably the cause of high-frequency microsatellite instability (MSI-H) sporadic CRCs, its role in microsatellite stable (MSS) tumors is debated. The majority of MSS CRCs demonstrate chromosomal instability (CIN) with frequent loss of heterozygosity (LOH) at key tumor suppressor genes. We hypothesized that the majority of sporadic CRCs without CIN would be associated with CIMP. METHODS: We tested 126 sporadic CRCs for MSI and LOH and categorized tumors into MSI, LOH, or MSI-/LOH- subgroups. Methylation status was evaluated using 6 CIMP-related markers (MINT1, MINT2, MINT31, p16(INK4alpha), p14(ARF), and hMLH1) and 6 tumor suppressor genes (PTEN, TIMP3, RUNX3, HIC1, APC, and RARbeta2). BRAF V600E mutation analysis was performed using allele-specific polymerase chain reaction and DNA sequencing. RESULTS: We observed frequent methylation at all 12 loci in all CRCs. BRAF V600E mutations correlated with the MSI (P < .0001) and MSI-/LOH- (P = .03) subgroups. MSI and MSI-/LOH- tumors exhibited more promoter methylation than CRCs with LOH (P < .0001). We also found an inverse correlation between the frequencies of methylation and LOH (rho = -0.36; P < .0001). CONCLUSIONS: The associations between methylation frequencies at CIMP-related markers and MSI or MSI-/LOH- sporadic CRCs suggest that the majority of these tumors evolve through CIMP. These findings suggest that CIN and CIMP represent 2 independent and inversely related mechanisms of genetic and epigenetic instability in sporadic CRCs and confirm that MSI cancers arise as a consequence of CIMP.

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Published In

Gastroenterology

DOI

ISSN

0016-5085

Publication Date

January 2007

Volume

132

Issue

1

Start / End Page

127 / 138

Location

United States

Related Subject Headings

  • Proto-Oncogene Proteins B-raf
  • Promoter Regions, Genetic
  • Point Mutation
  • Phenotype
  • Middle Aged
  • Male
  • Loss of Heterozygosity
  • Humans
  • Genes, Tumor Suppressor
  • Gene Expression Regulation, Neoplastic
 

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Goel, A., Nagasaka, T., Arnold, C. N., Inoue, T., Hamilton, C., Niedzwiecki, D., … Boland, C. R. (2007). The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer. Gastroenterology, 132(1), 127–138. https://doi.org/10.1053/j.gastro.2006.09.018
Goel, Ajay, Takeshi Nagasaka, Christian N. Arnold, Toru Inoue, Cody Hamilton, Donna Niedzwiecki, Carolyn Compton, et al. “The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer.Gastroenterology 132, no. 1 (January 2007): 127–38. https://doi.org/10.1053/j.gastro.2006.09.018.
Goel A, Nagasaka T, Arnold CN, Inoue T, Hamilton C, Niedzwiecki D, et al. The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer. Gastroenterology. 2007 Jan;132(1):127–38.
Goel, Ajay, et al. “The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer.Gastroenterology, vol. 132, no. 1, Jan. 2007, pp. 127–38. Pubmed, doi:10.1053/j.gastro.2006.09.018.
Goel A, Nagasaka T, Arnold CN, Inoue T, Hamilton C, Niedzwiecki D, Compton C, Mayer RJ, Goldberg R, Bertagnolli MM, Boland CR. The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer. Gastroenterology. 2007 Jan;132(1):127–138.
Journal cover image

Published In

Gastroenterology

DOI

ISSN

0016-5085

Publication Date

January 2007

Volume

132

Issue

1

Start / End Page

127 / 138

Location

United States

Related Subject Headings

  • Proto-Oncogene Proteins B-raf
  • Promoter Regions, Genetic
  • Point Mutation
  • Phenotype
  • Middle Aged
  • Male
  • Loss of Heterozygosity
  • Humans
  • Genes, Tumor Suppressor
  • Gene Expression Regulation, Neoplastic