The diagnosis of sessile serrated adenomas (SSAs) is challenging, and there is a great deal of interobserver variability amongst pathologists in differentiating SSAs from hyperplastic polyps (HPPs). The aim of this study was (i) to assess the utility of epigenetic changes such as DNA methylation in differentiating SSAs from HPPs and (ii) to identify common methylation based molecular markers potentially useful for early detection of premalignant neoplastic lesions of gastrointestinal tract. A total of 97 primary patient adenoma samples were obtained from The Johns Hopkins Hospital pathology archive with IRB approval and HIPAA compliance. We analyzed the promoter associated CpG island methylation status of 17 genes using nested multiplex methylation specific PCR (MSP). Methylation of CDX2, hMLH1 and TLR2 was detected in SSAs and SSAs with dysplasia but not in HPPs. A subset of genes including EVL, GATAs (4 and 5), HIN-1, SFRPs (1, 2, 4 and 5), SOX17 and SYNE1 were methylated frequently in all premalignant gastrointestinal adenomas including tubular adenomas, villous adenomas, SSAs and SSAs with dysplasia but infrequently in non-premalignant polyps such as HPPs. Methylation of CDX2, hMLH1 and TLR2 may be of diagnostic utility in differentiating, histologically challenging cases of SSAs from HPPs. Genes such as EVL, GATAs, HIN-1, SFRPs, SOX17 and SYNE1, which are frequently methylated in all types of tested premalignant adenomas, may be useful as biomarkers in stool-based strategies for early detection of these adenomas and CRCs in future.
Purpose Little information is available on genetic and epigenetic changes in duodenal adenocarcinomas. The purpose was to identify possible subsets of duodenal adenocarcinomas based on microsatellite instability (MSI), DNA methylation, mutations in the KRAS and BRAF genes, clinicopathologic features, and prognosis. Experimental Design Demographics, tumor characteristics and survival were available for 99 duodenal adenocarcinoma patients. Testing for KRAS and BRAF mutations, MSI, MLH1 methylation and CpG island methylator phenotype (CIMP) status was performed. A Cox proportional hazard model was built to predict survival. Results CIMP+ was detected in 27 of 99 (27.3%) duodenal adenocarcinomas, and was associated with MSI (P = 0.011) and MLH1 methylation (P < 0.001), but not with KRAS mutations (P = 0.114), as compared to CIMP− tumors. No BRAF V600E mutation was detected. Among the CIMP+ tumors, 15 (55.6%) were CIMP+/MLH1-unmethylated (MLH1-U). Kaplan-Meier analysis showed tumors classified by CIMP, CIMP/MLH1 methylation status or CIMP/MSI status could predict overall survival (OS; P = 0.047, 0.002, and 0.002, respectively), while CIMP/MLH1 methylation status could also predict time-to-recurrence (TTR; P = 0.016). In multivariate analysis, CIMP/MLH1 methylation status showed a significant prognostic value regarding both OS (P < 0.001) and TTR (P = 0.023). Patients with CIMP+/MLH1-U tumors had the worst OS and TTR. Conclusions Our results demonstrate existence of CIMP in duodenal adenocarcinomas. The combination of CIMP+/MLH1-U appears to be independently associated with poor prognosis in patients with duodenal adenocarcinomas. This study also suggests that BRAF mutations are not involved in duodenal tumorigenesis, MSI or CIMP development.
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