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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2019.00724

DNA methylation biomarkers predict objective responses to PD-1/PD-L1 inhibition blockade

 Gang Xue1,  Jianghui Xiong2*, Ze-Jia Cui1,  Zhihuang Hu3,  Xiong-Hui Zhou1, Yuexing Zhu4, Ying Chen4,  Fengji Liang2, Da-nian Tang5, Bing-yang Huang6, Hong-Yu Zhang1 and Xiyu Yuan7*
  • 1College of informatics, Huazhong Agricultural University, China
  • 2State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, China
  • 3Department of Medical Oncology, Fudan University Shanghai Cancer Center, China
  • 4Space Institute of Southern China, China
  • 5Beijing Hospital, China
  • 6Department of Cardiothoracic Surgery, Strategic Support Force Medical Center of PLA, China
  • 7Dongguan People’s Hospital, China

Immune checkpoint inhibitor (ICI) treatment could bring long-lasting clinical benefits to patients with metastatic cancer. However, only a small proportion of patients respond to PD-1/PD-L1 blockade, so predictive biomarkers are needed. Here, based on DNA methylation profiles and the objective response rates (ORRs) of PD-1/PD-L1 inhibition therapy, we identified 269 CpG sites and developed an initial CpG-based model by Lasso to predict ORRs. Notably, as measured by the area under the receiver operating characteristic curve (AUC), our model can produce better performance (AUC = 0.92) than both a model based on tumor mutational burden (TMB) (AUC = 0.77) and a previously reported TMB model (AUC = 0.71). In addition, most CpGs also have additional synergies with TMB, which can achieve a higher prediction accuracy when joined with TMB. Furthermore, we identified CpGs that are associated with TMB at the individual level. DNA methylation modules defined by protein networks, KEGG pathways and ligand-receptor gene pairs are also associated with ORRs. This method suggested novel immuno-oncology targets that might be beneficial when combined with PD-1/PD-L1 blockade. Thus, DNA methylation studies might hold great potential for individualized PD1/PD-L1 blockade or combinatory therap

Keywords: PD-1/PD-L1 inhibition therapy, Objective response rate, DNA Methylation, biomarkers, LASSO model

Received: 05 Mar 2019; Accepted: 10 Jul 2019.

Edited by:

Yun Liu, School of Basic Medical Sciences, Fudan University, China

Reviewed by:

Erietta Stelekati, University of Pennsylvania, United States
Chang Sun, Shaanxi Normal University, China  

Copyright: © 2019 Xue, Xiong, Cui, Hu, Zhou, Zhu, Chen, Liang, Tang, Huang, Zhang and Yuan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Jianghui Xiong, State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China, xiongjh77@163.com
Mr. Xiyu Yuan, Dongguan People’s Hospital, Dongguan, 523059, China, 15816818820@qq.com