Open AccessSignificance of gene mutations in the Wnt signaling pathway in traditional serrated adenomas of the colon and rectum
Author(s) -
Hiroyuki Nakanishi,
Takeshi Sawada,
Yasuharu Kaizaki,
Ryosuke Ota,
Hiromu Suzuki,
Eiko Yamamoto,
Hironori Aoki,
Makoto Eizuka,
Kenkei Hasatani,
Naoki Takahashi,
Shinji Inagaki,
Masahide Ebi,
Hiroyuki Kato,
Eiji Kubota,
Hiromi Kataoka,
Satoru Takahashi,
Takashi Tokino,
Toshinari Minamoto,
Tamotsu Sugai,
Yasushi Sasaki
Publication year - 2020
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0229262
Subject(s) - wnt signaling pathway , carcinogenesis , cancer research , methylation , colorectal cancer , biology , hyperplastic polyp , mutation , dna methylation , exon , epigenetics , cancer , gene , genetics , gene expression , colonoscopy
Recent studies have shown that colorectal serrated lesions, which include sessile serrated adenomas (SSAs) and traditional serrated adenomas (TSAs), are precursors of colorectal cancer. However, the molecular mechanisms underlying the carcinogenesis, particularly in TSAs, remain largely uncharacterized. To clarify their molecular and clinicopathological characteristics, we performed mutation and methylation analyses of cancer-associated genes in 78 serrated lesions, including TSAs, SSAs and microvesicular hyperplastic polyps. Target exon sequence analysis was performed with 39 genes, including genes known to be frequently mutated in colorectal cancers and/or serrated lesions. We also used bisulfite pyrosequencing to assess the methylation status of various cancer-associated genes and marker genes of the CpG island methylator phenotype (CIMP). The prevalence of mutations in genes associated with Wnt signaling was significantly higher in TSAs than SSAs (65% vs. 28%, p < 0.01). Among those, RNF43 mutations were observed in 38% of TSAs and 17% of SSAs. In immunohistochemical studies of 39 serrated lesions, the prevalence of abnormal nuclear β-catenin accumulation was significantly higher in TSAs (57%) than SSAs (8%) (P = 0.01). SMOC1 methylation was detected in 54% of TSAs but in no SSAs (p < 0.01). Additionally, SMOC1 methylation was more prevalent among TSAs with KRAS mutation (82%) than with BRAF mutation (38%, p = 0.03). Lesions with CIMP-high or RNF43 mutations were detected only in TSAs with BRAF mutation, suggesting two distinct carcinogenic pathways in TSAs. Mutations in genes associated with Wnt signaling play a greater role in the carcinogenesis of TSAs than SSAs.