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Subtypes of the Type II Pit Pattern Reflect Distinct Molecular Subclasses in the Serrated Neoplastic Pathway

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Abstract

Background

Colorectal serrated lesions (SLs) are important premalignant lesions whose clinical and biological features are not fully understood.

Aims

We aimed to establish accurate colonoscopic diagnosis and treatment of SLs through evaluation of associations among the morphological, pathological, and molecular characteristics of SLs.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgments

The authors thank Dr. William F. Goldman for editing the manuscript and Mutsumi Toyota and Tomo Hatahira for technical assistance.

Funding

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).

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Author notes

  1. Hironori Aoki, Eiichiro Yamamoto, and Hiro-o Yamano have contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biology, Sapporo Medical University School of Medicine, S1, W17, Chuo-ku, Sapporo, 060-8556, Japan

    Hironori Aoki, Eiichiro Yamamoto, Taku Harada, Akira Yorozu, Hiroshi Kitajima, Takeshi Niinuma, Masahiro Kai & Hiromu Suzuki

  2. Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan

    Eiichiro Yamamoto, Hiro-o Yamano & Hiroshi Nakase

  3. Department of Digestive Disease Center, Akita Red Cross Hospital, Akita, Japan

    Hiro-o Yamano, Tomoaki Kimura, Yoshihito Tanaka, Hiro-o Matsushita, Kenjiro Yoshikawa, Ryo Takagi, Eiji Harada, Michiko Nakaoka & Yuko Yoshida

  4. Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan

    Tamotsu Sugai & Makoto Eizuka

  5. Department of Gastroenterology, Teine-Keijinkai Hospital, Sapporo, Japan

    Taku Harada & Gota Sudo

  6. Center for Translational Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Masanori Nojima

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  1. Hironori Aoki
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  2. Eiichiro Yamamoto
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Corresponding author

Correspondence to Hiromu Suzuki.

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Aoki, H., Yamamoto, E., Yamano, Ho. et al. Subtypes of the Type II Pit Pattern Reflect Distinct Molecular Subclasses in the Serrated Neoplastic Pathway. Dig Dis Sci 63, 1920–1928 (2018). https://doi.org/10.1007/s10620-018-5016-5

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  • DOI: https://doi.org/10.1007/s10620-018-5016-5

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