Crosstalk of Histone and RNA Modifications Identified a Stromal-Activated Subtype with Poor Survival and Resistance to Immunotherapy in Gastric Cancer

Cheng Yuan; Junchang Zhang; Cuncan Deng; Yujian Xia; Bo Li; Sijun Meng; Xinghan Jin; Lvjia Cheng; Huafu Li; Changhua Zhang; Yulong He

doi:10.3389/fphar.2022.868830

Crosstalk of Histone and RNA Modifications Identified a Stromal-Activated Subtype with Poor Survival and Resistance to Immunotherapy in Gastric Cancer

Front Pharmacol. 2022 May 5:13:868830. doi: 10.3389/fphar.2022.868830. eCollection 2022.

Authors

Cheng Yuan^{1

2}, Junchang Zhang^{1

3}, Cuncan Deng^{1

2}, Yujian Xia⁴, Bo Li^{2

5}, Sijun Meng^{1

2}, Xinghan Jin^{1

3}, Lvjia Cheng⁶, Huafu Li⁷, Changhua Zhang^{1

2

5}, Yulong He^{1

2

3

5}

Affiliations

¹ Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
² Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
³ Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
⁴ Department of Thyroid Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
⁵ Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
⁶ Gastrointestinal Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China.
⁷ The Institute of Cancer Research, London, United Kingdom.

Abstract

Emerging evidence has revealed the pivotal role of epigenetic modifications in shaping the tumor microenvironment (TME). However, crosstalk between different modification types and their clinical relevance in cancers remain largely unexplored. In this study, using ChIP/MeRIP-seq data of seven human gastric cell lines, we systematically characterized the crosstalk of four epigenetic modification types including H3K4me1, H3K4me3, H3K27ac, and N6-methyladenosine (m6A) and identified a recurrent subtype with high FTO expression and low HDAC1 expression across three independent gastric cancer (GC) cohorts, which we named the epigenetic-modification-dysregulated (EMD) subtype. Patients of the EMD subtype were featured with poor survival, stromal activation, and immune suppression. Extensive relevance to clinical characteristics was observed in the EMD subtype, including the Lauren classification, MSI status, histological grade, TNM stage, the Asian Cancer Research Group classification, and the immune/fibrotic classification. An EMD score was then constructed using WGCNA and ssGSEA algorithms, to precisely recognize the EMD subtype and indicate prognosis and response to immunotherapy in multiple independent GC cohorts. Correlations of the EMD score with tumor mutation burden, tumor purity, aneuploidy score, tumorigenic pathways, TME characteristics, and FTO/HDAC1 ratio were measured. In vitro experiments were performed to demonstrate the correlation between FTO and the epithelial-mesenchymal transition pathway, which suggested FTO as a targetable vulnerability for GC patients with a high EMD score. Altogether, by comprehensively analyzing the epigenetic modification patterns of 1518 GC patients, we identified a novel stromal-activated subtype with poor survival and resistance to immunotherapy, which might benefit from the combined immune checkpoint inhibition therapy with FTO inhibition.

Keywords: gastric cancer; histone modification; immunotherapy; m6A; prognosis; tumor microenvironment.