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CpG Island Methylator Phenotype Associates with Low-Degree Chromosomal Abnormalities in Colorectal Cancer

Authors' Affiliations: ¹ Department of Microbiology and Immunology, Weill Medical College of Cornell University; ² Gertrude H. Sergievsky Center, Columbia University; ³ Department of Surgery, Colorectal Surgery Service, Memorial Sloan-Kettering Cancer Center; ⁴ Laboratory of Statistical Genetics, Rockefeller University, New York, New York; ⁵ Department of Molecular Biology, Princeton University, Princeton, New Jersey; and ⁶ Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China

Requests for reprints: Francis Barany, Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021. Phone: 212-746-6509; Fax: 212-746-8104; E-mail: barany{at}med.cornell.edu.

Purpose: Aberrant promoter methylation and genomic instability occur frequently during colorectal cancer development. CpG island methylator phenotype (CIMP) has been shown to associate with microsatellite instability, and BRAF mutation and is often found in the right-side colon. Nevertheless, the relative importance of CIMP and chromosomal instability (CIN) for tumorigenesis has yet to be thoroughly investigated in sporadic colorectal cancers.

Experimental Design: We determined CIMP in 161 primary colorectal cancers and 66 matched normal mucosae using a quantitative bisulfite/PCR/ligase detection reaction (LDR)/Universal Array assay. The validity of CIMP was confirmed in a subset of 60 primary tumors using MethyLight assay and five independent markers. In parallel, CIN was analyzed in the same study cohort using Affymetrix 50K Human Mapping arrays.

Results: The identified CIMP-positive cancers correlate with microsatellite instability (P = 0.075) and the BRAF mutation V600E (P = 0.00005). The array-based high-resolution analysis of chromosomal aberrations indicated that the degree of aneuploidy is spread over a wide spectrum among analyzed colorectal cancers. Whether CIN was defined by copy number variations in selected microsatellite loci (criterion 1) or considered as a continuous variable (criterion 2), CIMP-positive samples showed a strong correlation with low-degree chromosomal aberrations (P = 0.075 and P = 0.012, respectively). Similar correlations were observed when CIMP was determined by MethyLight assay (P = 0.001 and P = 0.013, respectively).

Conclusion: CIMP-positive tumors generally possess lower chromosomal aberrations, which may only be revealed using a genome-wide approach. The significant difference in the degree of chromosomal aberrations between CIMP-positive and the remainder of samples suggests that epigenetic (CIMP) and genetic (CIN) abnormalities may arise from independent molecular mechanisms of tumor progression.

Commentary

Colon Cancer: It's CIN or CIMP

Jean-Pierre Issa
Clin. Cancer Res. 2008 14: 5939-5940. [Abstract] [Full Text] [PDF]

This article has been cited by other articles:

				J.-P. Issa Colon Cancer: It's CIN or CIMP Clin. Cancer Res., October 1, 2008; 14(19): 5939 - 5940. [Abstract] [Full Text] [PDF]