Backgrounds and Aim: Field defect or field cancerization is thought to underlie multicentricity of cancer in patients who have multiple tumors in the same tissue type. The field defect in colorectal cancers (CRCs) is characterized by occurrence of synchronous or metachronous multiple tumors. Epigenetic changes have been proposed as mediators of this field defect in some cases. The aim of this study is to determine epigenetic and genetic characteristics in synchronous colorectal neoplasias (Sy-CRNs). Methods: We evaluated the methylation status of eight genes (MINT1, 2, 31, hMLH1, p16, p14, MGMT and ERα) using a quantitative bisulfite-pyrosequencing analysis and genetic alterations of BRAF and KRAS using pyrosequencing analysis and mutant allele-specific amplification, respectively, in 39 Sy-CRNs (10 cancer pairs and 9 cancer/adenoma pairs) and 69 sporadic colorectal cancers (S-CRCs). Results: Methylation levels of MGMT were significantly higher in Sy-CRNs than S-CRCs (30.3 % vs. 17.3%, P = .010). MINT31 methylation was significantly lower in Sy-CRNs than S-CRCs (5.5% vs. 12.2%, P = .016). However, there was no significant difference in methylation levels for the other genes between Sy-CRNs and S-CRCs. Methylation levels of MGMT with a sensitive assay tended to be higher in normal colonic samples with MGMT methylation in both tumors than samples without MGMT methylation in both tumors (26.7 % and 15.2 %, respectively; P = .334). There was no significant difference in the incidence of CIMP, KRAS and BRAF mutations between Sy-CRNs and S-CRCs. Nevertheless, we found significant correlations between tumor pairs for MGMT, MINT1, p16 and hMLH1 methylation (r = .640, P = .002; r = .732, P < .001; r = .614, P = .003; r = 979, P < .001, respectively), as well as for BRAF mutations (r = 0.840, P < .001). In paired samples of Sy-CRNs, the relative risk (RR) of finding concordant patterns of BRAF mutations was 8-fold higher than that of discordant patterns (1.35 vs 0.17, P = .092). Conclusions: Synchronous colorectal tumors are highly concordant for methylation of MGMT, MINT1, p16 and MLH1 as well as BRAF mutations, consistent with a molecular field defect that predisposes to specific sub-types of cancers. It remains to be determined whether this field defect is acquired or inherited.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA