The CpG Island Methylator Phenotype and Chromosomal Instability Are Inversely Correlated in Sporadic Colorectal Cancer

Ajay Goel, Takeshi Nagasaka, Christian N. Arnold, Toru Inoue, Cody Hamilton, Donna Niedzwiecki, Carolyn Compton, Robert J. Mayer, Richard Goldberg, Monica M. Bertagnolli, C. Richard Boland

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Abstract

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, p16INK4α, p14ARF, and hMLH1) and 6 tumor suppressor genes (PTEN, TIMP3, RUNX3, HIC1, APC, and RARβ2). 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 (ρ = -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.

Original languageEnglish (US)
Pages (from-to)127-138
Number of pages12
JournalGastroenterology
Volume132
Issue number1
DOIs
StatePublished - Jan 2007
Externally publishedYes

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Chromosomal Instability
CpG Islands
Loss of Heterozygosity
Colorectal Neoplasms
Phenotype
Methylation
Neoplasms
Tumor Suppressor Genes
Microsatellite Repeats
N-methylsuccinimide
Tumor Suppressor Protein p14ARF
Microsatellite Instability
Mutation
DNA Sequence Analysis
Epigenomics
Carcinogenesis
Alleles

ASJC Scopus subject areas

  • Gastroenterology

Cite this

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

The CpG Island Methylator Phenotype and Chromosomal Instability Are Inversely Correlated in Sporadic Colorectal Cancer. / Goel, Ajay; Nagasaka, Takeshi; Arnold, Christian N.; Inoue, Toru; Hamilton, Cody; Niedzwiecki, Donna; Compton, Carolyn; Mayer, Robert J.; Goldberg, Richard; Bertagnolli, Monica M.; Boland, C. Richard.

In: Gastroenterology, Vol. 132, No. 1, 01.2007, p. 127-138.

Research output: Contribution to journalArticle

Goel, A, Nagasaka, T, Arnold, CN, Inoue, T, Hamilton, C, Niedzwiecki, D, Compton, C, Mayer, RJ, Goldberg, R, Bertagnolli, MM & Boland, CR 2007, 'The CpG Island Methylator Phenotype and Chromosomal Instability Are Inversely Correlated in Sporadic Colorectal Cancer', Gastroenterology, vol. 132, no. 1, pp. 127-138. https://doi.org/10.1053/j.gastro.2006.09.018
Goel, Ajay ; Nagasaka, Takeshi ; Arnold, Christian N. ; Inoue, Toru ; Hamilton, Cody ; Niedzwiecki, Donna ; Compton, Carolyn ; Mayer, Robert J. ; Goldberg, Richard ; Bertagnolli, Monica M. ; Boland, C. Richard. / The CpG Island Methylator Phenotype and Chromosomal Instability Are Inversely Correlated in Sporadic Colorectal Cancer. In: Gastroenterology. 2007 ; Vol. 132, No. 1. pp. 127-138.
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AU - Nagasaka, Takeshi

AU - Arnold, Christian N.

AU - Inoue, Toru

AU - Hamilton, Cody

AU - Niedzwiecki, Donna

AU - Compton, Carolyn

AU - Mayer, Robert J.

AU - Goldberg, Richard

AU - Bertagnolli, Monica M.

AU - Boland, C. Richard

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