DNA methylation predicts recurrence from resected stage III proximal colon cancer

Abstract

BACKGROUND:In colorectal cancer (CRC), DNA methylation anomalies define distinct subgroups termed CpG island methylator phenotype 1 (CIMP1), CIMP2, and CIMP-negative. The role of this classification in predicting recurrence and disease-free survival (DFS) in resected stage III CRC was evaluated. METHODS: Sporadic cancers from 161 patients were analyzed. Bisulfite pyrosequencing was used to examine the methylation of 2 global DNA methylation markers (LINE-1, Alu) and 9 loci (MINT1, MINT2, MINT31, P16, hMLH1, P14, SFRP1, SFRP2, and WNT5A). Mutations in BRAF and KRAS were assayed. RESULTS: Gene hypermethylation clustered in discrete groups of patients, indicating the presence of CIMP. K-means clustering analysis identified 3 discrete subgroups: CIMP1 (n ¼ 22, 13.7%), associated with proximal location and BRAF mutations; CIMP2 (n ¼ 40, 24.8%), associated with KRAS mutations; and CIMP-negative (n ¼ 99, 61.5%), associated with distal location. In proximal CRC, CIMP1 was correlated with a higher recurrence rate (53% for CIMP1, 18% for CIMP2, and 26% for CIMP-negative) and a worse DFS (P ¼ .015). Also in proximal CRC, LINE-1 methylation was lower in patients whose cancer recurred compared with those whose cancer did not recur (P ¼ .049). In multivariate analysis, CIMP1 and low LINE1 methylation were independent prognostic factors for DFS in proximal CRC (P ¼ .008 for classification by K-means clustering analysis; P ¼ .040 for LINE-1 methylation status). CONCLUSIONS: DNA methylation is a useful biomarker of recurrence in resected stage III proximal but not distal CRC. However, as the number of CIMP1 cases was small in distal CRC, further study is required to validate our findings.

Long Interspersed Element-1 Methylation Level as a Prognostic Biomarker in Gastrointestinal Cancers

“…They observed an approximately fivefold difference in cancer-specific mortality, as LINE-1 methylation in the tumor genes ranged from high to low [14]. Subsequent studies have confirmed the relationship between LINE-1 hypomethylation and poor prognosis in resected colorectal cancers [15-18]. In addition, LINE-1 hypomethylation has been reported to correlate with unfavorable outcomes in colon cancer patients receiving oxaliplatin with fluorouracil and folinic acid adjuvant chemotherapy [19-21].…”

Relationship between LINE-1 hypomethylation and Helicobacter pylori infection in gastric mucosae

“…Consequently, LINE-1 methylation level is regarded as a surrogate marker of global DNA methylation [9]. Moreover, LINE-1 methylation levels can now be measured at high throughput and low cost using pyrosequencing technology [10][11][12]. Indeed, we have reported that LINE-1 hypomethylation has emerged as a promising prognostic or predictive biomarker in esophageal cancer and gastric cancer [13,14].…”

Gene discovery in familial cancer syndromes by exome sequencing: prospects for the elucidation of familial colorectal cancer type X

“…92 In addition to young onset (consistent with familial predisposition), colorectal cancers characterized by long interspersed element-1 hypomethylation consistently exhibited a poor prognosis. 93,94 Taken together, these findings further suggest molecular heterogeneity of familial colorectal cancer type X, with several possible molecular subtypes.…”