Differences in DNA Methylation Signatures Reveal Multiple Pathways of Progression From Adenoma to Colorectal Cancer

Luo, Yanxin; Wong, Chao Jen; Kaz, Andrew M.; Dzieciatkowski, Slavomir; Carter, Kelly; Morris, Shelli M.; Wang, Jianping; Willis, Joseph E.; Makar, Karen W.; Ulrich, Cornelia M.; Lutterbaugh, James; Shrubsole, Martha J.; Wang, Zheng; Markowitz, Sanford D.; Grady, William M.

doi:10.1053/j.gastro.2014.04.039

Cited by 180 publications

(214 citation statements)

References 48 publications

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“…However, we only analyzed a limited region [BLAST: chr5:112,175,118-112,176,026 (Feb. 2009 GRCh37/hg19 Assembly)] with the most prevalent APC mutations. Still, our results were similar to those of Luo et al 28 finding APC mutations in 29.7% of CRC and 27.8% of adenoma tissue samples using larger sample size and testing longer APC regions.…”

supporting

confidence: 92%

“…MethylCap-seq can test both promoter and gene body regions in the entire genome. For comparing previous and our DNA methylation results, the in silico analysis of Luo et al 28 data, also including adenomas besides CRC and NAT samples, was performed. Similarly to the work of Luo et al, 28 we compared a group of NAT samples to CRC and adenoma sample groups, instead of doing a pairwise comparison of CRC and NAT samples.…”

Section: Discussionmentioning

confidence: 99%

“…In silico DNA methylation analysis of WNT pathway genes CpG sites belonging to the significant DMRs in our MethylCap-sey study were searched using the Illumina BeadChip 450K array data sets from Luo et al 28 (GEO accession number: GSE48684; Table 3) and P-and Db-values were determined in CRC vs. NAT, AD vs. NAT, and CRC vs. AD comparisons.…”

Section: Dna Methylator Analysis Of Wnt Signaling Pathway Genesmentioning

confidence: 99%

“…Serrated adenoma samples-representing another neoplastic pathway of CRC development-were also profiled in several previous methylation projects. 23,[25][26][27] Illumina BeadChip technology is a frequently used method in global methylation studies 22,28,29 and allows the determination of the methylation status of >485,000 CpG sites at singlenucleotide resolution. Next generation sequencing of the methylated DNA regions, such as methyl capture sequencing (MethylCap-seq), is another option for genome-wide methylation analysis for revealing novel differentially methylated regions (DMRs).…”

Section: Introductionmentioning

confidence: 99%

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Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer

et al. 2016

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The WNT signaling pathway has an essential role in colorectal carcinogenesis and progression, which involves a cascade of genetic and epigenetic changes. We aimed to analyze DNA methylation affecting the WNT pathway genes in colorectal carcinogenesis in promoter and gene body regions using whole methylome analysis in 9 colorectal cancer, 15 adenoma, and 6 normal tumor adjacent tissue (NAT) samples by methyl capture sequencing. Functional methylation was confirmed on 5-aza-2 0 -deoxycytidine-treated colorectal cancer cell line datasets. In parallel with the DNA methylation analysis, mutations of WNT pathway genes (APC, b-catenin/CTNNB1) were analyzed by 454 sequencing on GS Junior platform. Most differentially methylated CpG sites were localized in gene body regions (95% of WNT pathway genes). In the promoter regions, 33 of the 160 analyzed WNT pathway genes were differentially methylated in colorectal cancer vs. normal, including hypermethylated AXIN2, CHP1, PRICKLE1, SFRP1, SFRP2, SOX17, and hypomethylated CACYBP, CTNNB1, MYC; 44 genes in adenoma vs. NAT; and 41 genes in colorectal cancer vs. adenoma comparisons. Hypermethylation of AXIN2, DKK1, VANGL1, and WNT5A gene promoters was higher, while those of SOX17, PRICKLE1, DAAM2, and MYC was lower in colon carcinoma compared to adenoma. Inverse correlation between expression and methylation was confirmed in 23 genes, including APC, CHP1, PRICKLE1, PSEN1, and SFRP1. Differential methylation affected both canonical and noncanonical WNT pathway genes in colorectal normal-adenoma-carcinoma sequence. Aberrant DNA methylation appears already in adenomas as an early event of colorectal carcinogenesis.

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supporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Dna Methylator Analysis Of Wnt Signaling Pathway Genesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer

et al. 2016

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“…Although the most effective treatment of CRC is surgery and adjuvant chemotherapy, patients with late-stage of colorectal cancer still have poor prognosis and the overall mortality of the disease is around 40% (Luo et al, 2014). Thus, chemoprevention has received attention as an effective approach to reduce incidence and malignancy of colorectal cancer.…”

Section: Introductionmentioning

confidence: 99%

Anti-Cancer Activity of the Flower Bud of Sophora japonica L. through Upregulating Activating Transcription Factor 3 in Human Colorectal Cancer Cells

Lee¹,

Park²,

Song³

et al. 2015

Korean Journal of Plant Resources

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-The flower buds of Sophora japonica L (SF), as a well-known traditional Chinese medicinal herb, have been used to treat bleeding-related disorders such as hematochezia, hemorrhoidal bleeding, dysfunctional uterine bleeding, and diarrhea. However, no specific anti-cancer effect and its molecular mechanism of SF have been described. Thus, we performed in vitro study to investigate if treatment of SF affects activating transcription factor 3 (ATF3) expression and ATF3-mediated apoptosis in human colorectal cancer cells. The effects of SF on cell viability and apoptosis were measured by MTT assay and Western blot analysis against cleaved poly (ADP-ribose) polymerase (PARP). ATF3 activation induced by SF was evaluated using Western blot analysis, RT-PCR and ATF3 promoter assay. SF treatment caused decrease of cell viability and increase of apoptosis in a dose-dependent manner in HCT116 and SW480 cells. Exposure of SF activated the levels of ATF3 protein and mRNA via transcriptional regulation in HCT116 and SW480 cells. Inhibition of extracellular signal-regulated kinases (ERK) 1/2 by PD98059 and p38 by SB203580 attenuated SF-induced ATF3 expression and transcriptional activation. Ectopic ATF3 overexpression accelerated SF-induced cleavage of PARP. These findings suggest that SF-mediated apoptosis may be the result of ATF3 expression through ERK1/2 and p38-mediated transcriptional activation.

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Epigenetic Mechanisms in Lynch Syndrome

Nieminen

Niskakoski

Peltomäki

2016

Encyclopedia of Life Sciences

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Lynch syndrome (LS) has been known for a century. The syndrome was originally recognised as a dominant predisposition to cancers of multiple organs, including those of the gastrointestinal tract and female reproductive organs. In 1993–1995, LS was linked to germline mutations in DNA (deoxyribonucleic acid) mismatch repair (MMR) genes MLH1 , MSH2 , MSH6 and PMS2 . Soon thereafter, promoter methylation as an alternative mechanism of DNA MMR gene inactivation was discovered. Such ‘epigenetic mutations’ (epimutations) may be somatic (e.g. biallelic methylation of MLH1 in sporadic microsatellite‐unstable cancers) or constitutional (monoallelic methylation of MLH1 or MSH2 in normal tissue, involving cells derived from all three germ layers and causing predisposition to LS cancers). To date, epigenetic mechanisms are known to operate at all stages of LS tumourigenesis, from constitutional predisposition to cancer initiation and progression, and involve DNA MMR genes as well as multiple other growth‐regulatory genes. This review discusses the role of epigenetic mechanisms in the pathogenesis of LS and more broadly, LS as a model of epigenetic mechanisms underlying common human cancers. Key Concepts Lynch syndrome (LS) is caused by mutations in one of the DNA mismatch repair genes; MLH1 , MSH2 , MSH6 or PMS2 . DNA methylation, miRNAs and histone modifications are involved in epigenetic regulation of MMR genes. Epigenetic regulation has been linked to constitutional predisposition, cancer initiation and progression in LS. MLH1 gene may be constitutionally affected by primary epimutation (has no known genetic basis and is usually not inherited) or secondary epimutation (associated with genetic cis ‐ or trans ‐acting alteration, which can be transmitted to offspring). EPCAM deletions may induce secondary epimutations of the MSH2 gene. MMR genes typically, but not always, require two hit inactivation for tumour initiation. LS spectrum tumours have epigenetic profiles characteristic of tumour type. Environmental factors interact with genetic and epigenetic factors, influencing LS phenotype.

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Differences in DNA Methylation Signatures Reveal Multiple Pathways of Progression From Adenoma to Colorectal Cancer

Cited by 180 publications

References 48 publications

Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer

Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer

Anti-Cancer Activity of the Flower Bud of Sophora japonica L. through Upregulating Activating Transcription Factor 3 in Human Colorectal Cancer Cells

Epigenetic Mechanisms in Lynch Syndrome

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