Article | Published:

Molecular Diagnostics

LGR5 expression predicts peritoneal recurrence after curative resection of primary colon cancer

British Journal of Cancervolume 120pages9961002 (2019) | Download Citation

Abstract

Background

The aim of this study was to clarify whether a cancer stem cell marker could be an indicator of post-operative peritoneal recurrence of colon cancer.

Methods

Expression of four putative markers (CD133, CD44 variant 6, aldehyde dehydrogenase-1 and leucine-rich repeating G-protein-coupled receptor-5 (LGR5)) was evaluated immunohistochemically in primary tumour samples from 292 patients who underwent curative resection for non-metastasised pT4 colon cancer at the University of Tokyo Hospital between 1997 and 2015.

Results

Peritoneal recurrence was significantly higher in LGR5-negative cases (5-year cumulative incidence: 27.5% vs. 14.4%, p = 0.037). Multivariable analysis confirmed that negative LGR5 expression was an independent risk factor for peritoneal recurrence (hazard ratio (HR) 2.79, p = 0.005) in addition to poor differentiation, positive lymph node metastasis, preoperative carcinoembryonic antigen > 5 ng/mL and anastomotic leakage. The addition of LGR5 significantly improved the predictive value of the multivariable model (net reclassification improvement: 0.186, p = 0.028: integrated discrimination improvement: 0.047, p = 0.008).

Conclusions

Negative LGR5 expression was a significant predictor of peritoneal recurrence in patients with pT4 colon cancer. Therefore, LGR5 might be a promising biomarker to identify patients at high risk of post-operative peritoneal metastasis.

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Acknowledgements

This research is supported by Grants-in-Aid for Scientific Research from Japan Society for the promotion of Science [grant numbers: 16K07143, 16K07161, 17K10620, 17K10621 and 17K10623], and the Project for Cancer Research and Therapeutic Evolution from the Japan Agency for Medical Research and Development [grant number: JP17cm0106502].

Author contributions

Hiroshi Nagata and S.I. made substantial contributions to conception and design of the study, as well as analysis and interpretation of data and drafting of the article; H.A., T.U. and J.K. significantly contributed to the pathological evaluation of specimens and revision of the paper; T.T., K.H. and K.K. participated in the interpretation of data and drafting of the article; M.F. and Hiroaki Nozawa contributed to conception of the study and critically revised the paper.

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Affiliations

  1. Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan

    • Hiroshi Nagata
    • , Soichiro Ishihara
    • , Junko Kishikawa
    • , Toshiaki Tanaka
    • , Keisuke Hata
    • , Kazushige Kawai
    •  & Hiroaki Nozawa
  2. Department of Pathology, The University of Tokyo, Tokyo, Japan

    • Hiroyuki Abe
    • , Tetsuo Ushiku
    •  & Masashi Fukayama

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study protocol was approved by the research ethics committee at the Graduate School of Medicine, the University of Tokyo (3252-(7)). The need for written consent was waved by the Board because of the retrospective nature of the study. The research was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments.

Data availability

The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.

Note

This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

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Correspondence to Hiroshi Nagata.

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https://doi.org/10.1038/s41416-019-0442-5