Sessile serrated adenoma shares similar genetic and epigenetic features with microsatellite unstable colon cancer in a location-dependent manner

Maeda, Takafumi; Suzuki, Koichi; Togashi, Kazutomo; Saito, Masaaki; Tsujinaka, Shingo; Kamiyama, Hidenori; Konishi, Fumio

doi:10.3892/etm.2011.249

Cited by 25 publications

(26 citation statements)

References 29 publications

(35 reference statements)

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“…This was similar to other reports where a majority of CIMP-H SSAs and HPs were proximally located [19, 27, 33]. We found that CIMP-H was significantly associated with BRAF mutant serrated polyps and a negative association existed between KRAS mutation and CIMP-H which was also observed in studies by O'Brien et al and Yang et al [19, 29].…”

Section: Discussionsupporting

confidence: 92%

The CIMP Phenotype inBRAFMutant Serrated Polyps from a Prospective Colonoscopy Patient Cohort

Fernando

Miranda

Worthley

et al. 2014

Gastroenterology Research and Practice

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Colorectal cancers arising via the serrated pathway are often associated with BRAF V600E mutation, CpG island methylator phenotype (CIMP), and microsatellite instability. Previous studies have shown a strong association between BRAF V600E mutation and serrated polyps. This study aims to evaluate CIMP status of all the serrated polyp subtypes and its association with functionally important genes such as MLH1, p16, and IGFBP7. CIMP status and methylation were evaluated using the real-time based MethyLight assay in 154 serrated polyps and 63 conventional adenomas. Results showed that CIMP-high serrated polyps were strongly associated with BRAF mutation and proximal colon. CIMP-high was uncommon in conventional adenomas (1.59%), occurred in 8.25% of hyperplastic polyps (HPs), and became common in sessile serrated adenomas (SSAs) (51.43%). MLH1 methylation was mainly observed in the proximal colon and was significantly associated with BRAF mutation and CIMP-high. The number of samples methylated for p16 and IGFBP7 was the highest in SSAs. The methylation panel we used to detect CIMP is highly specific for CIMP-high cancers. With this panel, we demonstrate that CIMP-high is much more common in SSAs than HPs. This suggests that CIMP-high correlates with increased risk of malignant transformation which was also observed in methylation of functionally important genes.

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Section: Discussionsupporting

confidence: 92%

The CIMP Phenotype inBRAFMutant Serrated Polyps from a Prospective Colonoscopy Patient Cohort

Fernando

Miranda

Worthley

et al. 2014

Gastroenterology Research and Practice

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“…Although we detected high levels of methylation accumulation in SSA/P, our data also suggested that DNA methylation accumulation was not completed by the adenoma stage, and the methylation of genes, including MLH1 , may increase during development from adenoma to cancer in the serrated pathway. Compared with our results, lower frequency of MLH1 methylation in SSA/P have been reported by other groups . This result might be explained, in part, by differences in the tumor size and histological appearance.…”

Section: Discussioncontrasting

confidence: 88%

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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“…It has been reported that distinct genetic and epigenetic features exist in the proximal SSA/p and the distal SSA/p . 14 Another possibility is that these left-sided polyps are in fact hyperplastic polyps with morphology indiscernible from SSA/p due to various factors (such as orientation, processing artifact etc.). Further study with more definitive standard is needed to clarify this issue, as the current biomarkers such as BRAF mutation is not specific enough to distinguish SSA/p from HP.…”

Section: Discussionmentioning

confidence: 99%

Loss of Hes1 Differentiates Sessile Serrated Adenoma/Polyp From Hyperplastic Polyp

Cui

Awadallah

Liu

et al. 2016

American Journal of Surgical Pathology

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Sessile serrated adenoma/polyp (SSA/p) is a precancerous lesion, and its differential diagnosis from hyperplastic polyp (HP) could be challenging in certain circumstances based on morphology alone. Hes1 is a downstream target of Notch signaling pathway and plays an important role in intestinal development by regulating differentiation of enterocytes. In this study, we evaluated the expression patterns of Hes1 in SSA/p and hyperplastic polyp (HP), and determine whether Hes1 immunostaining can help differentiate between these two entities. Serrated polyps with cytological dysplasia (sessile serrated adenoma with cytological dysplasia, tubular adenoma, and traditional serrated adenoma) were also studied. Hes1 is ubiquitously expressed in the nuclei of normal colon epithelial cells. The complete loss or a very weak expression of Hes1 is observed in the majority of the SSA/p in the study (58/63, 92%) compared to the normal expression of Hes1 in HP (35/35,100%). In SSA/p with cytological dysplasia, dysplastic area demonstrated cytoplasmic and/or nuclear staining for Hes1. Tubular adenoma and traditional serrated adenoma showed variability of Hes1 staining within the polyp with a mixed positive and negative staining pattern. Our study suggests that loss of Hes1 could be used as a sensitive and specific marker to differentiate SSA/p from HP, which helps the diagnosis in morphologically challenging cases.

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Sessile serrated adenoma shares similar genetic and epigenetic features with microsatellite unstable colon cancer in a location-dependent manner

Cited by 25 publications

References 29 publications

The CIMP Phenotype inBRAFMutant Serrated Polyps from a Prospective Colonoscopy Patient Cohort

The CIMP Phenotype inBRAFMutant Serrated Polyps from a Prospective Colonoscopy Patient Cohort

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

Loss of Hes1 Differentiates Sessile Serrated Adenoma/Polyp From Hyperplastic Polyp

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