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Identification of early genetic changes in well-differentiated intramucosal gastric carcinoma by target deep sequencing

  • Takashi Yoshida
  • Tatsuya Yamaguchi
  • Shinya MaekawaEmail author
  • Shinichi Takano
  • Toru Kuno
  • Keisuke Tanaka
  • Fumihiko Iwamoto
  • Yuya Tsukui
  • Shoji Kobayashi
  • Yukiko Asakawa
  • Hiroko Shindo
  • Mitsuharu Fukasawa
  • Yasuhiro Nakayama
  • Taisuke Inoue
  • Tomoyoshi Uetake
  • Masahiko Ohtaka
  • Tadashi Sato
  • Kunio Mochizuki
  • Nobuyuki Enomoto
Original Article

Abstract

Background and aims

The recent advancement of next-generation sequencing (NGS) has enabled the identification of cancer-related somatic aberrations in advanced gastric cancer. However, these remain unclear in early gastric cancers, especially in intramucosal gastric cancers.

Patients and methods

Thirty-one well-differentiated (tub1) intramucosal gastric cancers obtained by endoscopic submucosal dissection (ESD) from 29 patients were analyzed. After precise collection of tumors and non-tumors from formalin-fixed paraffin-embedded tissues using laser-captured microdissection (LCM), target sequencing analysis of 50 cancer-related genes was performed using an Ion-Proton sequencer.

Results

The most frequent hotspot mutation was found in TP53 (17 lesions, 54.8%) followed by the Wnt-signaling pathway genes, APC and CTNNB1 (6 lesions, 19.4%). The mutations in TP53 and the Wnt-signaling genes were mutually exclusive (p = 0.004). There was a tendency that H. pylori infection (p = 0.082) and macroscopic protrusion (p = 0.095) was associated with the presence of these mutations. Only 10 lesions (59%) among 17 lesions with proven TP53 mutations were positive for p53 immunostaining demonstrating the superiority of the mutational analysis. In addition, focal gene amplification of ERBB2 (16%) was found frequently in these early stage lesions.

Conclusions

Using LCM and NGS, mutations in TP53 and the Wnt-signaling pathway were frequently found and were mutually exclusive in the earliest stage of gastric carcinogenesis.

Keywords

Somatic mutations NGS LCM Well-differentiated intramucosal gastric carcinoma 

Notes

Acknowledgements

This study was supported by the Agency for Medical Research and Development (AMED) of Japan.

Compliance with ethical standards

Conflict of interest

We declare that we have no conflict of interest.

Ethical approval

This study was approved by the Human Ethics Review Committee of Yamanashi University Hospital.

Supplementary material

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Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2019

Authors and Affiliations

  • Takashi Yoshida
    • 1
  • Tatsuya Yamaguchi
    • 1
  • Shinya Maekawa
    • 1
    Email author
  • Shinichi Takano
    • 1
  • Toru Kuno
    • 1
  • Keisuke Tanaka
    • 1
  • Fumihiko Iwamoto
    • 1
  • Yuya Tsukui
    • 1
  • Shoji Kobayashi
    • 1
  • Yukiko Asakawa
    • 1
  • Hiroko Shindo
    • 1
  • Mitsuharu Fukasawa
    • 1
  • Yasuhiro Nakayama
    • 1
  • Taisuke Inoue
    • 1
  • Tomoyoshi Uetake
    • 1
  • Masahiko Ohtaka
    • 1
  • Tadashi Sato
    • 1
  • Kunio Mochizuki
    • 2
  • Nobuyuki Enomoto
    • 1
  1. 1.First Department of Internal Medicine, Faculty of MedicineUniversity of YamanashiChuoJapan
  2. 2.Department of Pathology, Faculty of MedicineUniversity of YamanashiChuoJapan

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