Identification of stem cell-related subtypes and risk scoring for gastric cancer based on stem genomic profiling

Renshen Xiang,Wei Song,Jincheng Fu,Jing Wu,Jun Ren,Tao Fu

doi:10.1186/s13287-021-02633-x

Renshen Xiang, Wei Song + Show 4 more

Open Access

https://doi.org/10.1186/s13287-021-02633-x

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Abstract

BackgroundAlthough numerous studies demonstrate the role of cancer stem cells in occurrence, recurrence, and distant metastases in gastric cancer (GC), little is known about the evolving genetic and epigenetic changes in the stem and progenitor cells. The purpose of this study was to identify the stem cell subtypes in GC and examine their clinical relevance.MethodsTwo publicly available datasets were used to identify GC stem cell subtypes, and consensus clustering was performed by unsupervised machine learning methods. The cancer stem cell (CSC) typing-related risk scoring (RS) model was established through multivariate Cox regression analysis.ResultsCross-platform dataset-based two stable GC stem cell subtypes, namely low stem cell enrichment (SCE_L) and high stem cell enrichment (SCE_H), were prudently identified. Gene set enrichment analysis revealed that the classical oncogenic pathways, immune-related pathways, and regulation of stem cell division were active in SCE_H; ferroptosis, NK cell activation, and post-mutation repair pathways were active in SCE_L. GC stem cell subtypes could accurately predict clinical outcomes in patients, tumor microenvironment cell-infiltration characteristics, somatic mutation landscape, and potential responses to immunotherapy, targeted therapy, and chemotherapy. Additionally, a CSC typing-related RS model was established; it was strongly independent and could accurately predict the patient’s overall survival.ConclusionsThis study demonstrated the complex oncogenic mechanisms underlying GC. The findings provide a basis and reference for the diagnosis and treatment of GC.

Highlights

Gastric cancer (GC) is one of the most common gastrointestinal malignancies with high incidence and mortality rates
cancer stem cell (CSC) have been successfully identified in several solid tumors, and a growing body of evidence shows that CSCs which arise from epigenetic mutations in the stem or progenitor cells account for 0.1% of tumor cells [5,6,7]
Differential expression and functional analyses of gastric cancer (GC) stem cell subtypes Based on the set criteria of |log2[fold change (FC)]|> 0.5 and a false discovery rate (FDR) < 0.05, we investigated the differentially expressed genes (DEGs) among GC stem cell subtypes in The Cancer Genome Atlas (TCGA) and GSE84437 cohorts

Summary

Introduction

Gastric cancer (GC) is one of the most common gastrointestinal malignancies with high incidence and mortality rates. As early as 1959, Makino et al [3] hypothesized that tumor cells may originate from cancer stem cells (CSCs). CSCs have strong repair ability after DNA damage and can maintain stable genetic inheritance [6, 7] regulated by complicated gene regulatory networks in the tumor microenvironment (TME) and tumor cells; these include the Hippo signaling [8], Hedgehog signaling [9], WNT/β-catenin, [10] and NK-kB signaling pathways [11]. Multi-directional differentiation leads to tumor heterogeneity, which in turn has important impacts on tumor recurrence, metastasis, and drug resistance [13, 14]. Numerous studies demonstrate the role of cancer stem cells in occurrence, recurrence, and distant metastases in gastric cancer (GC), little is known about the evolving genetic and epigenetic changes in the stem and progenitor cells. The purpose of this study was to identify the stem cell subtypes in GC and examine their clinical relevance

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