Dataset Information

Distinct patterns of DNA methylation in conventional adenomas involving the right and left colon.

ABSTRACT: Recent studies have shown two distinct non-CIMP methylation clusters in colorectal cancer, raising the possibility that DNA methylation, involving non-CIMP genes, may play a role in the conventional adenoma-carcinoma pathway. A total of 135 adenomas (65 left colon and 70 right colon) were profiled for epigenome-wide DNA methylation using the Illumina HumanMethylation450 BeadChip. A principal components analysis was performed to examine the association between variability in DNA methylation and adenoma location. Linear regression and linear mixed effects models were used to identify locus-specific differential DNA methylation in adenomas of right and left colon. A significant association was present between the first principal component and adenoma location (P=0.007), even after adjustment for subject age and gender (P=0.009). A total of 168 CpG sites were differentially methylated between right- and left-colon adenomas and these loci demonstrated enrichment of homeobox genes (P=3.0 × 10(-12)). None of the 168 probes were associated with CIMP genes. Among CpG loci with the largest difference in methylation between right- and left-colon adenomas, probes associated with PRAC (prostate cancer susceptibility candidate) gene showed hypermethylation in right-colon adenomas whereas those associated with CDX2 (caudal type homeobox transcription factor 2) showed hypermethylation in left-colon adenomas. A subgroup of left-colon adenomas enriched for current smokers (OR=6.1, P=0.004) exhibited a methylation profile similar to right-colon adenomas. In summary, our results indicate distinct patterns of DNA methylation, independent of CIMP genes, in adenomas of the right and left colon.

SUBMITTER: Koestler DC

PROVIDER: S-EPMC3880603 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Distinct patterns of DNA methylation in conventional adenomas involving the right and left colon.

Koestler Devin C DC Li Jing J Baron John A JA Tsongalis Gregory J GJ Butterly Lynn F LF Goodrich Martha M Lesseur Corina C Karagas Margaret R MR Marsit Carmen J CJ Moore Jason H JH Andrew Angeline S AS Srivastava Amitabh A

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20130719 1

Recent studies have shown two distinct non-CIMP methylation clusters in colorectal cancer, raising the possibility that DNA methylation, involving non-CIMP genes, may play a role in the conventional adenoma-carcinoma pathway. A total of 135 adenomas (65 left colon and 70 right colon) were profiled for epigenome-wide DNA methylation using the Illumina HumanMethylation450 BeadChip. A principal components analysis was performed to examine the association between variability in DNA methylation and a ...[more]

PMID: 23868178

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Project description:BackgroundRecent work led to recognize sessile serrated adenomas (SSA) as precursor to many of the sporadic colorectal cancers with microsatellite instability (MSI). However, comprehensive analyses of DNA methylation in SSA and MSI cancer have not been conducted.MethodsWith an array-based methylation sensitive amplified fragment length polymorphism (MS-AFLP) method we analyzed 8 tubular (TA) and 19 serrated (SSA) adenomas, and 14 carcinomas with (MSI) and 12 without (MSS) microsatellite instability. MS-AFLP array can survey relative differences in methylation between normal and tumor tissues of 9,654 DNA fragments containing all NotI sequences in the human genome.ResultsUnsupervised clustering analysis of the genome-wide hypermethylation alterations revealed no major differences between or within these groups of benign and malignant tumors regardless of their location in intergenic, intragenic, promoter, or 3' end regions. Hypomethylation was less frequent in SSAs compared with MSI or MSS carcinomas. Analysis of variance of DNA methylation between these four subgroups identified 56 probes differentially altered. The hierarchical tree of this subset of probes revealed two distinct clusters: Group 1, mostly composed by TAs and MSS cancers with KRAS mutations; and Group 2 with BRAF mutations, which consisted of cancers with MSI and MLH1 methylation (Group 2A), and SSAs without MLH1 methylation (Group 2B). AXIN2, which cooperates with APC and ?-catenin in Wnt signaling, had more methylation alterations in Group 2, and its expression levels negatively correlated with methylation determined by bisulfite sequencing. Within group 2B, low and high AXIN2 expression levels correlated significantly with differences in size (P = 0.01) location (P = 0.05) and crypt architecture (P = 0.01).ConclusionsSomatic methylation alterations of AXIN2, associated with changes in its expression, stratify SSAs according to some clinico-pathological differences. We conclude that hypermethylation of MLH1, when occurs in an adenoma cell with BRAF oncogenic mutational activation, drives the pathway for MSI cancer by providing the cells with a mutator phenotype. AXIN2 inactivation may contribute to this tumorigenic pathway either by mutator phenotype driven frameshift mutations or by epigenetic deregulation contemporary with the unfolding of the mutator phenotype.

Project description:Sessile serrated adenomas are now recognized as precursor lesions of a substantial subset of colorectal cancers arising via a so-called “serrated pathway”. However, their biological markers remain to be defined. The aim of our study was to identify differentially expressed genes in sessile serrated adenomas, hyperplastic polyps and tubular adenomas. Gene expression analysis demonstrated molecular differences between polyp types. Further studies using QRT-PCR on Cathepsin E demonstrated a significantly (p< 0.05) higher expression in sessile serrated adenomas as compared to both other polyp types. Trefoil Factor 1, showed the same trend of expression for sessile serrated adenomas as compared to hyperplastic polyps, and was significantly higher in both polyps compared to tubular adenomas. Immunohistochemistry for both proteins demonstrated strong cytoplasmic staining of abnormal crypts in all sessile serrated adenomas while staining in tubular adenomas and hyperplastic polyps was weak and focal. BRAF and KRAS mutation analysis were employed to further validate polyp discrimination. The findings demonstrated the positive association of the BRAF mutation, V600E, with sessile serrated adenomas and KRAS mutations with tubular adenomas (P<0.05). This study demonstrates CTSE and TFF1 over-expression in sessile serrated adenomas compared to both hyperplastic polyps and tubular adenomas. Keywords: colonic polyp tissue comparison, linear modelling, SSA Microarray analysis was performed on 13 SSAs and 11 TAs. SSAs were from 4 males and 9 females (mean age of 75) and TAs were from 5 males and 6 females (mean age of 72). Samples were directly hybridised to each other (SSA versus TA) or to a pooled normal control (SSA versus control). A linear model (Smyth 2004) was fitted to the data bringing together the three contrasts: SSA versus control, TA versus control and SSA versus TA. Human OligoLibrary (Compugen Human Oligo Library (v1) containing 18861 60-mer oligonucleotides, representing approximately 16,000 unique genes) by the Adelaide Microarray Centre (Australia) was used. Slides were scanned using a GenePix 3000B scanner (Axon Instruments, Sunnydale, CA), and the Spot package (CSIRO, Australia) was used to identify spots and estimate fore- and background intensities (using a morphological opening background estimator) (Yang, Buckley et al. 2001; Ritchie 2004). Data analysis was performed in R (www.r-project.org) using the Limma package of Bioconductor (Gentleman, Carey et al. 2004; Smyth 2004). Loess print tip method was used to correct for dye-bias and intensity within each group of adjacent spots printed by one pin (Yang, Dudoit et al. 2002). Linear modelling was performed with the Limma package of Bioconductor (Smyth 2004).

Project description:BACKGROUND:Single-incision laparoscopic right hemicolectomy (SILS) has long used in surgery for a long time. However, there is barely a systemic review related to the comparison between the SILS and the conventional laparoscopic right hemicolectomy (CLS) for the right colon cancer in the long term follow-up. Herein, we used the most recent articles to compare these two techniques by meta-analysis. METHODS:We searched PubMed, Web of Science, Cochrane Library and Wanfang databases to compare SILS with CLS for right colon cancer up to May 2019. The operative, postoperative, pathological and mid-term follow-up outcomes of nine studies were extracted and compared. RESULTS:A total of 1356 patients participated in 9 studies, while 653 patients were assigned to the SILS group and 703 patients were assigned to the CLS group. The patients' baselines in the SILS group were consistent with those in the CLS group. Compared to the CLS group, the SILS group had a shorter operation duration (SMD - 23.49, 95%CI - 36.71 to - 10.27, P < 0.001, chi-square = 24.11), shorter hospital stay (SMD - 0.76, 95% `CI - 1.07 to - 0.45, P < 0.001, chi-square = 9.85), less blood loss (SMD - 8.46, 95% CI - 14.59 to - 2.34; P < 0.05; chi-square = 2.26), smaller incision length (SMD - 1.60, 95% CI - 2.66 to - 0.55, P < 0.001; chi-square = 280.44), more lymph node harvested (SMD - 0.98, 95% CI - 1.79 to - 0.16, P < 0.05; chi-square = 4.61), and a longer proximal surgical edge (SMD - 0.51, 95% CI - 0.93 to - 0.09, P < 0.05; chi-square = 2.42). No significant difference was found in other indexes. After we removed a single large study, we performed another meta-analysis again. The operation duration in the SILS group was still better than that in the CLS group. CONCLUSION:SILS could be a faster and more reliable approach than CLS for the right colon cancer and could accelerate patient recovery, especially for patients with a low BMI.

Dataset Information

Distinct patterns of DNA methylation in conventional adenomas involving the right and left colon.

Publications

Distinct patterns of DNA methylation in conventional adenomas involving the right and left colon.

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