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

Abstract

BackgroundImmune 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.MethodsA 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.ResultsA 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 (ADHFE1, DOK6, GPR75, and MAP3K14-AS1) 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 (POU3F3, SYN2, and TMEM178A) had significantly poorer survival in the high-risk TMB samples than those in the low-risk TMB samples (P=0.016). CRC patients with low-risk scores combined with TMB levels represent a favorable survival.ConclusionsBy 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.

Down-regulated HHLA2 enhances neoadjuvant immunotherapy efficacy in patients with non-small cell lung cancer (NSCLC) with chronic obstructive pulmonary disease (COPD)

“…Down-regulated HHLA2 in NSCLC with COPD might improve the response to neoadjuvant immunotherapy by means of the enrichment of CD8 + CD103 + TRM. Previous research have demonstrated that lung cancer patients with COPD had certain characteristics that suggested they may benefit from immunotherapy, such as high TMB, high tumor neo-antigen burden (TNB), high mutation frequencies of immune-related genes like LRP1B and PREX2, and low mutation frequency of EGFR [21,22]. Furthermore, it has been reported that advanced NSCLC with COPD had a better overall survival (OS) and PFS compared to NSCLC without COPD when treated by immunotherapy [23].…”

Discovering methylation markers and development of a sense-antisense and dual-MGB probe PCR assay in plasma for colorectal cancer early detection

“…A number of studies [31][32][33][34][35] have demonstrated that the methylation levels of NTMT1 (whose antisense chain counterpart is C9orf50) and MAP3K14-AS1 can be employed for the screening and diagnosis of CRC. In particular, the study conducted by Sarah Ø Jensen et al [34].…”

“…indicated that the C9orf50 methylation assay exhibited a plasma sensitivity of 76% and speci city of 91% for CRC. Ludovic Barault and colleagues [35] demonstrated that the MAP3K14-AS1 methylation assay in plasma exhibited a sensitivity of 69.8% and a speci city of 100% for CRC. The dual-strand technique has been proven to enhance the performance of markers in previous studies [14,15].…”

Discovering methylation markers and development of a sense-antisense and dual-MGB probe PCR assay in plasma for colorectal cancer early detection

“…A number of studies [31][32][33][34][35] have demonstrated that the methylation levels of NTMT1 (whose antisense chain counterpart is C9orf50) and MAP3K14-AS1 can be employed for the screening and diagnosis of CRC. In particular, the study conducted by Sarah Ø Jensen et al [34] indicated that the C9orf50 methylation assay exhibited a plasma sensitivity of 76% and specificity of 91% for CRC.…”

“…In particular, the study conducted by Sarah Ø Jensen et al [34] indicated that the C9orf50 methylation assay exhibited a plasma sensitivity of 76% and specificity of 91% for CRC. Ludovic Barault and colleagues [35] demonstrated that the MAP3K14-AS1 methylation assay in plasma exhibited a sensitivity of 69.8% and a specificity of 100% for CRC. The dual-strand technique has been proven to enhance the performance of markers in previous studies [14,15].…”