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Digestive Diseases and Sciences

, Volume 63, Issue 7, pp 1920–1928 | Cite as

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

  • Hironori Aoki
  • Eiichiro Yamamoto
  • Hiro-o Yamano
  • Tamotsu Sugai
  • Tomoaki Kimura
  • Yoshihito Tanaka
  • Hiro-o Matsushita
  • Kenjiro Yoshikawa
  • Ryo Takagi
  • Eiji Harada
  • Michiko Nakaoka
  • Yuko Yoshida
  • Taku Harada
  • Gota Sudo
  • Makoto Eizuka
  • Akira Yorozu
  • Hiroshi Kitajima
  • Takeshi Niinuma
  • Masahiro Kai
  • Masanori Nojima
  • Hiromu SuzukiEmail author
  • Hiroshi Nakase
Original Article

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.

Keywords

Colorectal neoplasms Colonoscopy Mutation DNA methylation Serrated lesion Pit pattern 

Notes

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).

Compliance with ethical standards

Conflict of interest

All authors have no conflict of interest to declare.

Supplementary material

10620_2018_5016_MOESM1_ESM.pdf (4.5 mb)
Supplementary material 1 (PDF 4611 kb)
10620_2018_5016_MOESM2_ESM.pdf (46 kb)
Supplementary material 2 (PDF 46 kb)
10620_2018_5016_MOESM3_ESM.pdf (47 kb)
Supplementary material 3 (PDF 47 kb)
10620_2018_5016_MOESM4_ESM.pdf (41 kb)
Supplementary material 4 (PDF 40 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Hironori Aoki
    • 1
  • Eiichiro Yamamoto
    • 1
    • 2
  • Hiro-o Yamano
    • 2
    • 3
  • Tamotsu Sugai
    • 4
  • Tomoaki Kimura
    • 3
  • Yoshihito Tanaka
    • 3
  • Hiro-o Matsushita
    • 3
  • Kenjiro Yoshikawa
    • 3
  • Ryo Takagi
    • 3
  • Eiji Harada
    • 3
  • Michiko Nakaoka
    • 3
  • Yuko Yoshida
    • 3
  • Taku Harada
    • 1
    • 5
  • Gota Sudo
    • 5
  • Makoto Eizuka
    • 4
  • Akira Yorozu
    • 1
  • Hiroshi Kitajima
    • 1
  • Takeshi Niinuma
    • 1
  • Masahiro Kai
    • 1
  • Masanori Nojima
    • 6
  • Hiromu Suzuki
    • 1
    Email author
  • Hiroshi Nakase
    • 2
  1. 1.Department of Molecular BiologySapporo Medical University School of MedicineSapporoJapan
  2. 2.Department of Gastroenterology and HepatologySapporo Medical University School of MedicineSapporoJapan
  3. 3.Department of Digestive Disease CenterAkita Red Cross HospitalAkitaJapan
  4. 4.Department of Molecular Diagnostic PathologyIwate Medical UniversityMoriokaJapan
  5. 5.Department of GastroenterologyTeine-Keijinkai HospitalSapporoJapan
  6. 6.Center for Translational Research, The Institute of Medical ScienceThe University of TokyoTokyoJapan

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