AUTHOR=Huang Hao , Cao Weifan , Long Zhiping , Kuang Lei , Li Xi , Feng Yifei , Wu Yuying , Zhao Yang , Chen Yinggang , Sun Peng , Peng Panxin , Zhang Jinli , Yuan Lijun , Li Tianze , Hu Huifang , Li Gairui , Yang Longkun , Zhang Xing , Hu Fulan , Sun Xizhuo , Hu Dongsheng 

TITLE=DNA methylation-based patterns for early diagnostic prediction and prognostic evaluation in colorectal cancer patients with high tumor mutation burden

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.1030335

DOI=10.3389/fonc.2022.1030335

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Immune checkpoint inhibitor (ICI) therapy has proven to be a promising treatment for colorectal cancer (CRC). We aim to investigate the relationship between DNA methylation and tumor mutation burden (TMB) by integrating genomic and epigenetic profiles to precisely identify clinical benefit populations and to evaluate the effect of ICI therapy.</p></sec><sec><title>Methods</title><p>A total of 536 CRC tissues from the Cancer Genome Atlas (TCGA) with mutation data were collected and subjected to calculate TMB. 80 CRC patients with high TMB and paired normal tissues were selected as training sets and developed the diagnostic and prognostic methylation models, respectively. In the validation set, the diagnostic model was validated in our in-house 47 CRC tissues and 122 CRC tissues from the Gene Expression Omnibus (GEO) datasets, respectively. And a total of 38 CRC tissues with high TMB from the COLONOMICS dataset verified the prognostic model.</p></sec><sec><title>Results</title><p>A positive correlation between differential methylation positions and TMB level was observed in TCGA CRC cohort (r=0.45). The diagnostic score that consisted of methylation levels of four genes (<italic>ADHFE1</italic>, <italic>DOK6</italic>, <italic>GPR75</italic>, and <italic>MAP3K14-AS1</italic>) showed high diagnostic performance in the discovery (AUC=1.000) and two independent validation (AUC=0.946, AUC=0.857) datasets. Additionally, these four genes showed significant positive correlations with NK cells. The prognostic score containing three genes (<italic>POU3F3</italic>, <italic>SYN2</italic>, and <italic>TMEM178A</italic>) had significantly poorer survival in the high-risk TMB samples than those in the low-risk TMB samples (<italic>P</italic>=0.016). CRC patients with low-risk scores combined with TMB levels represent a favorable survival.</p></sec><sec><title>Conclusions</title><p>By integrating analyses of methylation and mutation data, it is suggested that DNA methylation patterns combined with TMB serve as a novel potential biomarker for early screening in more high-TMB populations and for evaluating the prognostic effect of CRC patients with ICI therapy.</p></sec>