Subtypes of the Type II Pit Pattern Reflect Distinct Molecular Subclasses in the Serrated Neoplastic Pathway
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Colorectal serrated lesions (SLs) are important premalignant lesions whose clinical and biological features are not fully understood.
We aimed to establish accurate colonoscopic diagnosis and treatment of SLs through evaluation of associations among the morphological, pathological, and molecular characteristics of SLs.
A total of 388 premalignant and 18 malignant colorectal lesions were studied. Using magnifying colonoscopy, microsurface structures were assessed based on Kudo’s pit pattern classification system, and the Type II pit pattern was subcategorized into classical Type II, Type II-Open (Type II-O) and Type II-Long (Type II-L). BRAF/KRAS mutations and DNA methylation of CpG island methylator phenotype (CIMP) markers (MINT1, − 2, − 12, − 31, p16, and MLH1) were analyzed through pyrosequencing.
Type II-O was tightly associated with sessile serrated adenoma/polyps (SSA/Ps) with BRAF mutation and CIMP-high. Most lesions with simple Type II or Type II-L were hyperplastic polyps, while mixtures of Type II or Type II-L plus more advanced pit patterns (III/IV) were characteristic of traditional serrated adenomas (TSAs). Type II-positive TSAs frequently exhibited BRAF mutation and CIMP-low, while Type II-L-positive TSAs were tightly associated with KRAS mutation and CIMP-low. Analysis of lesions containing both premalignant and cancerous components suggested Type II-L-positive TSAs may develop into KRAS-mutated/CIMP-low/microsatellite stable cancers, while Type II-O-positive SSA/Ps develop into BRAF-mutated/CIMP-high/microsatellite unstable cancers.
These results suggest that Type II subtypes reflect distinct molecular subclasses in the serrated neoplasia pathway and that they could be useful hallmarks for identifying SLs at high risk of developing into CRC.
KeywordsColorectal neoplasms Colonoscopy Mutation DNA methylation Serrated lesion Pit pattern
The authors thank Dr. William F. Goldman for editing the manuscript and Mutsumi Toyota and Tomo Hatahira for technical assistance.
This study was supported in part by Grant-in-Aid for Scientific Research (C) from the Japan Society for Promotion of Science (JSPS KAKENHI 15K08973, E. Yamamoto), Grant-in-Aid for Scientific Research (B) from the Japan Society for Promotion of Science (JSPS KAKENHI 15H04299, H. Suzuki) and Grants-in-Aid for Young Investigators (B) from Japan Society for Promotion of Science (JSPS KAKENHI 15K18431, T. Harada; JSPS KAKENHI 15K19339, H. Aoki), the Japanese Foundation for Research and Promotion of Endoscopy (JFE) Grant (E. Yamamoto), the Takeda Science Foundation (E. Yamamoto).
Compliance with ethical standards
Conflict of interest
All authors have no conflict of interest to declare.
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