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Stomach
Original research
Dissecting transcriptional heterogeneity in primary gastric adenocarcinoma by single cell RNA sequencing
  1. Min Zhang1,2,
  2. Shuofeng Hu1,3,
  3. Min Min2,
  4. Yanli Ni2,
  5. Zheng Lu2,
  6. Xiaotian Sun2,4,
  7. Jiaqi Wu1,3,
  8. Bing Liu1,2,
  9. Xiaomin Ying1,3,
  10. Yan Liu2
  1. 1 Academy of Military Medical Sciences, Beijing, China
  2. 2 The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
  3. 3 Center for Computational Biology, Institute of Military Cognition and Brain Sciences, Academy of Military Medical Sciences, Beijing, China
  4. 4 Department of internal medicine, Beijing South Medical District of Chinese PLA General Hospital, Beijing, China
  1. Correspondence to Prof Yan Liu, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100071, China; liuyan1799{at}126.com; Prof Xiaomin Ying, Center for Computational Biology, Institute of Military Cognition and Brain Sciences, Academy of Military Sciences, Beijing, 100850, China; yingxmbio{at}foxmail.com; Prof Bing Liu, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100071, China; bingliu17{at}yahoo.com

Abstract

Objective Tumour heterogeneity represents a major obstacle to accurate diagnosis and treatment in gastric adenocarcinoma (GA). Here, we report a systematic transcriptional atlas to delineate molecular and cellular heterogeneity in GA using single-cell RNA sequencing (scRNA-seq).

Design We performed unbiased transcriptome-wide scRNA-seq analysis on 27 677 cells from 9 tumour and 3 non-tumour samples. Analysis results were validated using large-scale histological assays and bulk transcriptomic datasets.

Results Our integrative analysis of tumour cells identified five cell subgroups with distinct expression profiles. A panel of differentiation-related genes reveals a high diversity of differentiation degrees within and between tumours. Low differentiation degrees can predict poor prognosis in GA. Among them, three subgroups exhibited different differentiation grade which corresponded well to histopathological features of Lauren’s subtypes. Interestingly, the other two subgroups displayed unique transcriptome features. One subgroup expressing chief-cell markers (eg, LIPF and PGC) and RNF43 with Wnt/β-catenin signalling pathway activated is consistent with the previously described entity fundic gland-type GA (chief cell-predominant, GA-FG-CCP). We further confirmed the presence of GA-FG-CCP in two public bulk datasets using transcriptomic profiles and histological images. The other subgroup specifically expressed immune-related signature genes (eg, LY6K and major histocompatibility complex class II) with the infection of Epstein-Barr virus. In addition, we also analysed non-malignant epithelium and provided molecular evidences for potential transition from gastric chief cells into MUC6 + TFF2 + spasmolytic polypeptide expressing metaplasia.

Conclusion Altogether, our study offers valuable resource for deciphering gastric tumour heterogeneity, which will provide assistance for precision diagnosis and prognosis.

  • gastric cancer
  • molecular pathology
  • endoscopic gastrostomy
  • epithelial cells
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/gutjnl-2019-320368

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    Footnotes

    • MZ, SH and MM contributed equally.

    • BL, XY and YL contributed equally.

    • Contributors MZ designed the experiments, collected the biopsies, analysed the data and wrote the manuscript. SH was responsible for data acquisition, analysis and interpretation, and writing the manuscript. MM collected the biopsies. YN was responsible for FACS sorting. YL, XY and BL were responsible for the study concept, design, interpretation and revising the manuscript.

    • Funding This work was supported by National Key R&D Program of China (Grant No. 2017YFC0908300), Natural Science Foundation of Beijing Municipality (Grant No. 7192201), Outstanding Youth Training Fund of the Chinese PLA General Hospital (Grant No. 2019-JQPY-001).

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were involved in the design, conduct, reporting or dissemination plans of this research. Refer to the ‘Methods’ section in online supplementary materials for further details.

    • Patient consent for publication Obtained.

    • Ethics approval The study was approved by the the ethical review community of the Fifth Medical Center of Chinese PLA General Hospital (No. ky-2017-8-11). All study participants provided written informed consent.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available in a public, open access repository. Data are available on reasonable request. The accession number for the raw data reported in this paper have been deposited in the Genome Sequence Archive (GSA) under accession number HRA000051 that can be accessed at: http://bigd.big.ac.cn/gsa-human/