Molecular patterns in the evolution of serrated lesion of the colorectum

Gaiser, Timo; Meinhardt, Sandra; Hirsch, Daniela; Killian, Jonathan Keith; Gaedcke, Jochen; Jo, Peter; Ponsa, Immaculada; Miró, Rosa; Rüschoff, Josef; Seitz, Gerhard; Hu, Yue; Camps, Jordi; Ried, Thomas

doi:10.1002/ijc.27869

Cited by 30 publications

(27 citation statements)

References 47 publications

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“…A quantitative methylation analysis revealed that SSA/P showed high‐methylation epigenotype, and was thus considered to be a precursor lesion of high‐methylation CRC, whereas TSA clearly showed intermediate‐methylation epigenotype. Consistent with our report, Gaiser et al . found similar methylation profiles in SSA/P and MSI‐high CRC, whereas TSA also revealed aberrant methylation pattern, but clustered more heterogeneously and closer to microsatellite‐stable CRCs.…”

Section: Discussionsupporting

confidence: 92%

Genetic and epigenetic aberrations occurring in colorectal tumors associated with serrated pathway

Shimizu

Fukuyo

Ohata

et al. 2015

Intl Journal of Cancer

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To clarify molecular alterations in serrated pathway of colorectal cancer (CRC), we performed epigenetic and genetic analyses in sessile serrated adenoma/polyps (SSA/P), traditional serrated adenomas (TSAs) and high‐methylation CRC. The methylation levels of six Group‐1 and 14 Group‐2 markers, established in our previous studies, were analyzed quantitatively using pyrosequencing. Subsequently, we performed targeted exon sequencing analyses of 126 candidate driver genes and examined molecular alterations that are associated with cancer development. SSA/P showed high methylation levels of both Group‐1 and Group‐2 markers, frequent BRAF mutation and occurrence in proximal colon, which were features of high‐methylation CRC. But TSA showed low‐methylation levels of Group‐1 markers, less frequent BRAF mutation and occurrence at distal colon. SSA/P, but not TSA, is thus considered to be precursor of high‐methylation CRC. High‐methylation CRC had even higher methylation levels of some genes, e.g., MLH1, than SSA/P, and significant frequency of somatic mutations in nonsynonymous mutations (p < 0.0001) and insertion/deletions (p = 0.002). MLH1‐methylated SSA/P showed lower methylation level of MLH1 compared with high‐methylation CRC, and rarely accompanied silencing of MLH1 expression. The mutation frequencies were not different between MLH1‐methylated and MLH1‐unmethylated SSA/P, suggesting that MLH1 methylation might be insufficient in SSA/P to acquire a hypermutation phenotype. Mutations of mismatch repair genes, e.g., MSH3 and MSH6, and genes in PI3K, WNT, TGF‐β and BMP signaling (but not in TP53 signaling) were significantly involved in high‐methylation CRC compared with adenoma, suggesting importance of abrogation of these genes in serrated pathway.

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Section: Discussionsupporting

confidence: 92%

Genetic and epigenetic aberrations occurring in colorectal tumors associated with serrated pathway

Shimizu

Fukuyo

Ohata

et al. 2015

Intl Journal of Cancer

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“…Recent studies suggest that CIMP CRCs are derived from sessile serrated adenomas [32] , a CRC precursor lesion exhibiting unique morphologic features and epigenetic characteristics [33, 34, 35] . Prior studies have shown that up to 30% of serrated adenomas have a CIMP methylation pattern and that tubular adenomas are rarely CIMP [33] .…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2014

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Background & Aims Genetic and epigenetic alterations contribute to the pathogenesis of colorectal cancer (CRC). There is considerable molecular heterogeneity among colorectal tumors, which appears to arise as polyps progress to cancer. This heterogeneity results in different pathways to tumorigenesis. Although epigenetic and genetic alterations have been detected in conventional tubular adenomas, little is known about how these affect progression to CRC. We compared methylomes of normal colon mucosa, tubular adenomas, and colorectal cancers to determine how epigenetic alterations might contribute to cancer formation. Methods We conducted genome-wide array-based studies and comprehensive data analyses of aberrantly methylated loci in 41 normal colon tissue, 42 colon adenomas, and 64 cancers using HumanMethylation450 arrays. Results We found genome-wide alterations in DNA methylation in the non-tumor colon mucosa adjacent to tubular adenomas and cancers. Three classes of cancers and 2 classes of adenomas were identified based on their DNA methylation patterns. The adenomas separated into classes of high-frequency methylation (adenoma-H), and low-frequency methylation (adenoma-L). Within the adenoma-H class a subset of adenomas had mutant KRAS. Additionally, the adenoma-H class had DNA methylation signatures similar to those of cancers with low or intermediate levels of methylation, whereas the adenoma-L class had methylation signatures similar to that of non-tumor colon tissue. The CpGs sites that were differentially methylated in these signatures are located in intragenic and intergenic regions. Conclusions Genome-wide alterations in DNA methylation occur during early stages of progression of tubular adenomas to cancer. These findings reveal heterogeneity in the pathogenesis of colorectal cancer, even at the adenoma step of the process.

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“…The high frequency of serrated polyps with MLH1 gene promoter methylation in individuals with MSI CRC suggests the presence of a serrated pathway in colorectal carcinogenesis [ 23 ] . More recently, genetic and epigenetic profi les of a variety of colorectal polyps have demonstrated that sessile serrated adenomas/polyps may be precursor lesions for MSI CRCs and follow the CIMP pathway [ 24 ] . Little is known about the CRCs that are without methylation of any promoter CGIs.…”

Section: Hypermethylation Of Cpg Islandmentioning

confidence: 99%