Serrated adenoma is a recently described entity characterized by having combined architectural features of hyperplastic polyps and classical adenoma. To understand the role of gene regulation in the progression of the serrated neoplasia pathway, we examined the methylation profiles of the promoter regions of 19 genes, DNA ploidy, and mutator phenotype status. In all, 40 sporadic, classical serrated adenomas were pathologically reviewed and divided into four pathologic groups according to their histologic grades. Methylation-specific PCR was performed using primers for p16, hMLH1, RASSF1A, APC, HIC-1, DAPK, MGMT, SLC5A8, RB1, HCadherin, E-Cadherin, TIMP3, PTEN, THBS1, LKB1, p14, p15, FHIT, and VHL. Dual flow-cytometric analyses using cytokeratin and DAPI and MSI studies using BAT26 were also performed. Methylation was observed in 2.5-82.5% (mean 33.9%) of the CpG islands in the promoter regions of 16 genes. The tumors with higher histologic grades, including carcinomas, showed more extensive methylation compared to those with lower grades, and serrated adenomas in the right colon showed more frequent methylation than those in the left (Po0.05). Tumor-specific promoter methylation of SLC5A8 was observed in 33 (82.5%) of the serrated adenomas. Aneuploidization with near-diploid DNA indices was detected in four out of 28 cases examined (14.3%); two were low-grade serrated adenomas and two were carcinomas in the left colon. The high mutator phenotype was not observed in any of the cases examined. Our results indicate that: (1) aberrant, widespread methylation of CpG islands increases with the histological progression of serrated adenomas; (2) methylation of SLC5A8 is an early event; and (3) additional methylation of the p16, p14, MGMT, TIMP3, and FHIT genes are important tumorigenic steps in the serrated neoplasia pathway.

Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) is rarely found in the large intestine. Because of its rarity, the underlying epigenetic and genetic changes in the pathogenesis and prognostic factors have yet to be well established. For this purpose, methylation profiles and API2/MALT1 fusion in marginal zone B-cell lymphoma of MALT in the colorectum were studied and compared with treatment outcomes. For methylation analyses, 7 independent CpG islands (p15, p16, DAP kinase, hMLH1, MINT1, MINT2, and MINT31) were examined and RT-PCR for detection of API2/MALT1 fusion transcripts were performed in 15 colorectal marginal zone B-cell lymphoma of MALT in a single institution. Marginal zone B-cell lymphomas of MALT from both gastric and colorectal locations were also examined. In methylation analyses (n ¼ 13), 8 of 13 (62%) cases were classified as CIMP (CpG island methylator phenotype)-positive. Methylation was more frequently observed in cases with advanced disease stages than with earlier stages; an average of two methylated loci for earlier stages (IE or IIE) versus four loci in advanced ones (IVE; P ¼ 0.02). The estimated 5-year progression-free survival was 42% for CIMP-positive and 100% for CIMP-negative cases (P ¼ 0.03). API2/MALT1 fusion transcripts were found in two of nine cases (22%). In two cases with concurrent gastric and colorectal involvement of marginal zone B-cell lymphoma of MALT, methylation patterns and API2/MALT1 fusion results were different by location. Our results suggest that methylation profiles define a clinically more aggressive subgroup and multiclonal origin for marginal zone B-cell lymphoma of MALT with multiorgan involvement.

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