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Epigenetic-Genetic Interactions in the APC/WNT, RAS/RAF, and P53 Pathways in Colorectal Carcinoma

Authors' Affiliations: ¹ Department of Pathology, Division of Pathology and Laboratory Medicine; ² Department of Leukemia, Division of Cancer Medicine; and ³ Department of Biostatistics and Applied Mathematics, Division of Quantitative Sciences, The University of Texas M. D. Anderson Cancer Center; ⁴ Department of Pathology, St. Luke's Episcopal Hospital, Houston, Texas; ⁵ Department of Clinical Laboratory Science, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan; and ⁶ Department of Pathology, The University of Hong Kong Queen Mary Hospital, Pokfulam, Hong Kong

Requests for reprints: Stanley R. Hamilton, Division of Pathology and Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 085, Houston, TX 77030. Phone: 713-792-2040; Fax: 713-792-4094; E-mail: shamilto{at}mdanderson.org.

Purpose: Early events in colorectal tumorigenesis include mutation of the adenomatous polyposis coli (APC) gene and epigenetic hypermethylation with transcriptional silencing of the O⁶-methylguanine DNA methyltransferase (MGMT), human mut L homologue 1 (hMLH1), and P16/CDKN2A genes. Epigenetic alterations affect genetic events: Loss of MGMT via hypermethylation reportedly predisposes to guanine-to-adenine or cytosine-to-thymine (G:CA:T) transition mutations in KRAS and P53, and silencing of hMLH1 leads to high levels of microsatellite instability (MSI-H)/mutator phenotype, suggesting that epigenetic-genetic subtypes exist.

Experimental Design: We evaluated the relationships of aberrant methylation of APC, MGMT, hMLH1, P16, N33, and five MINTs to mutations in APC, KRAS, BRAF, and P53 in 208 colorectal carcinomas.

Results: We found that APC hypermethylation was age related (P = 0.04), in contrast to the other genes, and did not cluster with CpG island methylator phenotype (CIMP) markers. Hypermethylation of APC concurrently with either MGMT or hMLH1 was strongly associated with occurrence of G-to-A transitions in APC [odds ratio (OR), 26.8; P < 0.0002 from multivariable logic regression model], but C-to-T transitions had no associations. There was no relationship of hypermethylation of any gene, including MGMT, with G-to-A or C-to-T transitions in KRAS or P53, although APC hypermethylation was associated with P53 mutation (P < 0.0002). CIMP with MSI-H due to hMLH1 hypermethylation, or CIMP with loss of MGMT expression in non–MSI-H tumors, was associated with BRAF mutation (OR, 4.5; P < 0.0002). CIMP was also associated with BRAF V600E T-to-A transversion (OR, 48.5; P < 0.0002).

Conclusions: Our findings suggest that the heterogeneous epigenetic dysregulation of promoter methylation in various genes is interrelated with the occurrence of mutations, as manifested in epigenetic-genetic subgroups of tumors.