Molecular characteristics of colorectal serrated polyps and hyperplastic polyps

Abstract

The serrated neoplasia pathway of colorectal carcinogenesis is characterized by BRAF mutation and aberrant DNA methylation, which have not been reported on Korean patients. The aim of this study was to investigate BRAF mutation and DNA methylation in colorectal serrated polyps and the right colon.Between 2005 and 2013, 146 colon polyps (47 tubular adenomas [TAs], 53 traditional serrated adenomas [TSAs], 17 sessile serrated adenomas/polyps [SSAs], and 29 hyperplastic polyps in the proximal colon [PHPs]) were collected from patients. Paraffin-embedded colon polyp tissue was used for DNA extraction. BRAF V600E mutation was identified through polymerase chain reaction (PCR) and pyrosequencing assay. The methylation status of the long interspersed nucleotide element-1, insulin-like growth factor binding protein 7 (IGFBP7), mutL homolog 1 (hMLH1), and CD133 genes were evaluated through disulfite conversion, PCR, and pyrosequencing assay.BRAF V600E mutation was found in 2.1% of TAs, 47.2% of TSAs, 41.2% of SSAs, and 20.7% of PHPs. TSA and SSA had higher BRAF mutation rates than did TA (P < 0.0001). TSA had higher BRAF mutation rates than did PHP (P = 0.018). IGFBP7 hypermethylation was found in 17% of TAs, 37.7% of TSAs, 88.2% of SSAs, and 37.5% of PHPs. TSA and SSA had higher hypermethylation of IGFBP7 than did TA (P = 0.021 and P < 0.0001, respectively). SSA had higher hypermethylation of IGFBP7 than did PHP (P = 0.002). hMLH1 hypermethylation was found in 2.1% of TAs, 5.7% of TSAs, 0% of SSAs, and 0% of PHPs. CD133 hypermethylation was found in 21.3% of TAs, 9.4% of TSAs, 35.3% of SSAs, and 17.4% of PHPs.BRAF mutation and methylation in TSA and SSA are different from those in PHP in Koreans. These findings suggested that PHP may have different molecular characteristics compared with other serrated polyps.

Significance of gene mutations in the Wnt signaling pathway in traditional serrated adenomas of the colon and rectum

“…IGFBP7 has been shown to play a central role in BRAF-induced senescence and to be a direct target of TP53 [47]. Although methylation of IGFBP7 has been investigated in specific histological types of serrated lesions [10,48], IGFBP7 methylation status has not been compared between these two TSA subtypes. In addition to these differences in genetic and epigenetic alterations, the difference in the prevalence of β-catenin expression further supports there being two different neoplastic pathways for TSAs.…”

DNA methylation changes that precede onset of dysplasia in advanced sessile serrated adenomas

“…MLH1 warrants separate discussion as its role in SSA progression is well established. Previous studies have demonstrated MLH1 methylation is detectable in otherwise unremarkable SSAs, ranging from 0.0 to 89.5% [13, 28, 31, 32, 54–65]. The cause for this large variation is uncertain but has been attributed to patient ethnicity [58], patient age [13, 60], lesion site [31, 55, 58] and primer choice [58, 66].…”