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Title: A Novel DNA Repair Gene Signature for Immune Checkpoint Inhibitor-Based Therapy in Gastric Cancer

Abstract

Gastric cancer is a heterogeneous group of diseases with only a fraction of patients responding to immunotherapy. The relationships between tumor DNA damage response, patient immune system and immunotherapy have recently attracted attention. Accumulating evidence suggests that DNA repair landscape is a significant factor in driving response to immune checkpoint blockade (ICB) therapy. In this study, to explore new prognostic and predictive biomarkers for gastric cancer patients who are sensitive and responsive to immunotherapies, we developed a novel 15-DNA repair gene signature (DRGS) and its related scoring system and evaluated the efficiency of the DRGS in discriminating different molecular and immune characteristics and therapeutic outcomes of patients with gastric adenocarcinoma, using publicly available datasets. The results demonstrated that DRGS high score patients showed significantly better therapeutic outcomes for ICB compared to DRGS low score patients (p < 0.001). Integrated analysis of multi-omics data demonstrated that the patients with high DRGS score were characteristic of high levels of anti-tumor lymphocyte infiltration, tumor mutation burden (TMB) and PD-L1 expression, and these patients exhibited a longer overall survival, as compared to the low-score patients. Results obtained from HPA and IHC supported significant dysregulation of the genes in DRGS in gastric cancer tissues, andmore » a positive correlation in protein expression between DRGS and PD-L1. Therefore, the DRGS scoring system may have implications in tailoring immunotherapy in gastric cancers. A preprint has previously been published (Yuan et al., 2021).« less

Authors:
 [1];  [1];  [1];  [1];  [2];  [1];  [1];  [1];  [3];  [4];  [1];  [4];  [1]
+ Show Author Affiliations
  1. Nanjing Univ. (China)
  2. Berkeley-Nanjing Research Center, Nanjing (China)
  3. Univ. of California, Berkeley, CA (United States)
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
OSTI Identifier:
1896676
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Frontiers in Cell and Developmental Biology
Additional Journal Information:
Journal Volume: 10; Journal ID: ISSN 2296-634X
Publisher:
Frontiers Media S.A.
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; gastric cancer; immunotherapy; immune checkpoint blockade; immune checkpoint inhibitors; DNA repair gene signature; prognostic biomarker; score system

Citation Formats

Yuan, Binbin, Jiang, Chengfei, Chen, Lingyan, Wen, Lihui, Cui, Jinlong, Chen, Min, Zhang, Shu, Zhou, Lin, Cai, Yimeng, Mao, Jian-Hua, Zou, Xiaoping, Hang, Bo, and Wang, Pin. A Novel DNA Repair Gene Signature for Immune Checkpoint Inhibitor-Based Therapy in Gastric Cancer. United States: N. p., 2022. Web. doi:10.3389/fcell.2022.893546.
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Yuan, Binbin, Jiang, Chengfei, Chen, Lingyan, Wen, Lihui, Cui, Jinlong, Chen, Min, Zhang, Shu, Zhou, Lin, Cai, Yimeng, Mao, Jian-Hua, Zou, Xiaoping, Hang, Bo, & Wang, Pin. A Novel DNA Repair Gene Signature for Immune Checkpoint Inhibitor-Based Therapy in Gastric Cancer. United States. https://doi.org/10.3389/fcell.2022.893546
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Yuan, Binbin, Jiang, Chengfei, Chen, Lingyan, Wen, Lihui, Cui, Jinlong, Chen, Min, Zhang, Shu, Zhou, Lin, Cai, Yimeng, Mao, Jian-Hua, Zou, Xiaoping, Hang, Bo, and Wang, Pin. Mon . "A Novel DNA Repair Gene Signature for Immune Checkpoint Inhibitor-Based Therapy in Gastric Cancer". United States. https://doi.org/10.3389/fcell.2022.893546. https://www.osti.gov/servlets/purl/1896676.
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@article{osti_1896676,
title = {A Novel DNA Repair Gene Signature for Immune Checkpoint Inhibitor-Based Therapy in Gastric Cancer},
author = {Yuan, Binbin and Jiang, Chengfei and Chen, Lingyan and Wen, Lihui and Cui, Jinlong and Chen, Min and Zhang, Shu and Zhou, Lin and Cai, Yimeng and Mao, Jian-Hua and Zou, Xiaoping and Hang, Bo and Wang, Pin},
abstractNote = {Gastric cancer is a heterogeneous group of diseases with only a fraction of patients responding to immunotherapy. The relationships between tumor DNA damage response, patient immune system and immunotherapy have recently attracted attention. Accumulating evidence suggests that DNA repair landscape is a significant factor in driving response to immune checkpoint blockade (ICB) therapy. In this study, to explore new prognostic and predictive biomarkers for gastric cancer patients who are sensitive and responsive to immunotherapies, we developed a novel 15-DNA repair gene signature (DRGS) and its related scoring system and evaluated the efficiency of the DRGS in discriminating different molecular and immune characteristics and therapeutic outcomes of patients with gastric adenocarcinoma, using publicly available datasets. The results demonstrated that DRGS high score patients showed significantly better therapeutic outcomes for ICB compared to DRGS low score patients (p < 0.001). Integrated analysis of multi-omics data demonstrated that the patients with high DRGS score were characteristic of high levels of anti-tumor lymphocyte infiltration, tumor mutation burden (TMB) and PD-L1 expression, and these patients exhibited a longer overall survival, as compared to the low-score patients. Results obtained from HPA and IHC supported significant dysregulation of the genes in DRGS in gastric cancer tissues, and a positive correlation in protein expression between DRGS and PD-L1. Therefore, the DRGS scoring system may have implications in tailoring immunotherapy in gastric cancers. A preprint has previously been published (Yuan et al., 2021).},
doi = {10.3389/fcell.2022.893546},
journal = {Frontiers in Cell and Developmental Biology},
number = ,
volume = 10,
place = {United States},
year = {Mon May 23 00:00:00 EDT 2022},
month = {Mon May 23 00:00:00 EDT 2022}
}
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Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.3389/fcell.2022.893546
Copyright Statement
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Figures / Tables:

FIGURE 1 FIGURE 1 : DNA repair genes and construction of the DRGS scoring system. (A) Identification of 15 common genes among the 219 DNA repair genes that are differentially expressed in both TCGA-STAD (Tumor n = 375, Normal n = 32) and GSE30727 (Tumor n = 30, Normal n = 30);more » (B) PCA analysis was used as a dimensionality reduction method to obtain the 1st dimension correlation coefficients of the 15 repair genes. DEGs: Differentially expressed genes.« less
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