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. 2016 Jun 7;7(23):35106-18.
doi: 10.18632/oncotarget.9044.

Assessment of epigenetic alterations in early colorectal lesions containing BRAF mutations

Takeshi Sawada  1   2 , Eiichiro Yamamoto  1   3 , Hiro-O Yamano  4 , Masanori Nojima  5 , Taku Harada  1 , Reo Maruyama  1 , Masami Ashida  1 , Hironori Aoki  1 , Hiro-O Matsushita  4 , Kenjiro Yoshikawa  4 , Eiji Harada  4 , Yoshihito Tanaka  4 , Shigenori Wakita  6 , Takeshi Niinuma  1 , Masahiro Kai  1 , Makoto Eizuka  7 , Tamotsu Sugai  7 , Hiromu Suzuki  1
Affiliations

Assessment of epigenetic alterations in early colorectal lesions containing BRAF mutations

Takeshi Sawada et al. Oncotarget. .

Abstract

To clarify the molecular and clinicopathological characteristics of colorectal serrated lesions, we assessed the DNA methylation of cancer-associated genes in a cohort of BRAF-mutant precancerous lesions from 94 individuals. We then compared those results with the lesions' clinicopathological features, especially colorectal subsites. The lesions included hyperplastic polyps (n = 16), traditional serrated adenomas (TSAs) (n = 15), TSAs with sessile serrated adenomas (SSAs) (n = 6), SSAs (n = 49) and SSAs with dysplasia (n = 16). The prevalence of lesions exhibiting the CpG island methylator phenotype (CIMP) was lower in the sigmoid colon and rectum than in other bowel subsites, including the cecum, ascending, transverse and descending colon. In addition, several cancer-associated genes showed higher methylation levels within lesions in the proximal to sigmoid colon than in the sigmoid colon and rectum. These results indicate that the methylation status of lesions with BRAF mutation is strongly associated with their location, histological findings and neoplastic pathways. By contrast, no difference in aberrant DNA methylation was observed in normal-appearing background colonic mucosa along the bowel subsites, which may indicate the absence of an epigenetic field defect.

Keywords: BRAF; CpG island methylator phenotype; colorectal cancer; methylation; serrated lesion.

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Conflict of interest statement

All authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Methylation profiles in BRAF-mutant lesions
A. Methylation of CIMP markers and CIMP status in lesions in the right colon (from cecum to transverse colon) and the left colon (from descending colon to sigmoid colon). B. Methylation status in BRAF-mutant lesions in the cecum (C) and ascending (A), transverse (T), descending (D) and sigmoid (S) colon and rectum (R). C. Frequencies of CIMP and MLH1 methylation in BRAF-mutant lesions in the indicated bowel subsites.
Figure 2
Figure 2
A. Frequencies of CIMP and MLH1 methylation in lesions with the indicated histological findings: HP, hyperplastic polyp; IM, intermediate; TSA, traditional serrated adenoma; SSA, sessile serrated adenoma; CD, cytological dysplasia; HGD, high-grade dysplasia. B. Frequencies of CIMP and MLH1 methylation in BRAF-mutant lesions with indicated diameters.
Figure 3
Figure 3. Summaries of the bisulfite pyrosequencing results from BRAF-mutant lesions
Shown are the levels of methylation of indicated genes A–H. and LINE-1 I. in lesions in the cecum (C) and ascending (A), transverse (T), descending (D) and sigmoid (S) colon and rectum (R). *P < 0.05, **P < 0.01, ***P < 0.001.
Figure 4
Figure 4. Summaries of bisulfite pyrosequencing results in normal-appearing mucosa adjacent to BRAF-mutant lesions
Shown are levels of methylation of the indicated genes A–C. and LINE-1 D. in the cecum (C) and ascending (A), transverse (T), descending (D) and sigmoid (S) colon and rectum (R).
Figure 5
Figure 5. Representative histopathological images of the major serrated lesion subtypes
A. Hyperplastic polyp (HP). B. Sessile serrated adenoma (SSA). C. Traditional serrated adenoma (TSA). D. TSA with SSA (TSA+SSA). E. SSA with cytological dysplasia (SSA+CD). F. SSA with high-grade dysplasia (SSA+HGD).
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