Dataset Information

Tumor Expression Quantitative Trait Methylation Screening Reveals Distinct CpG Panels for Deconvolving Cancer Immune Signatures.

ABSTRACT: DNA methylation signatures in tumors could serve as reliable biomarkers that are accessible in archival tissues for tracking the epigenetic dynamics shaped by both cancer cells and the tumor microenvironment. However, given the ultrahigh dimensionality and noncollapsible nature of the data, it remains challenging to screen all CpG sites to identify the most promising marker panels. In this article, we introduce the concept of tumor-based expression quantitative trait methylation (eQTM) for the prioritization and systematic mining of predictive biomarkers. In melanoma as a disease model, eQTM CpGs and genes represent new and efficient candidate targets to be investigated for both prognostic and immune status monitoring purposes. Three cis-eQTM CpGs (cg07786657, cg12446199, and cg00027570) were strongly associated with and can serve as surrogate biomarkers for the tumor immune cytolytic activity score (CYT). In addition, multiple eQTM genes could be further exploited for predicting immunoregulatory phenotypes. A targeted gene panel analysis identified one eQTM in TCF7 (cg25947408) as a novel candidate biomarker for uncoupling overall T-cell differentiation and exhaustion status in a tumor. The prognostic significance of this eQTM as an independent signature to CYT was validated by both The Cancer Genome Atlas and Moffitt melanoma cohort data. Overall, eQTMs represent a mechanistically distinct class of potential biomarkers that can be used to predict patient prognosis and immune status.

Significance

This study provides a novel and promising approach to identify targeted epigenetic biomarkers in cancer and will spur further analysis in tumor immune phenotyping.

SUBMITTER: Yu X

PROVIDER: S-EPMC9064917 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

Tumor Expression Quantitative Trait Methylation Screening Reveals Distinct CpG Panels for Deconvolving Cancer Immune Signatures.

Yu Xiaoqing X Cen Ling L Chen Y Ann YA Markowitz Joseph J Shaw Timothy I TI Tsai Kenneth Y KY Conejo-Garcia Jose R JR Wang Xuefeng X

Cancer research 20220501 9

DNA methylation signatures in tumors could serve as reliable biomarkers that are accessible in archival tissues for tracking the epigenetic dynamics shaped by both cancer cells and the tumor microenvironment. However, given the ultrahigh dimensionality and noncollapsible nature of the data, it remains challenging to screen all CpG sites to identify the most promising marker panels. In this article, we introduce the concept of tumor-based expression quantitative trait methylation (eQTM) for the p ...[more]

PMID: 35176128

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Project description:A fundamental challenge in the post-genome era is to understand and annotate the consequences of genetic variation, particularly within the context of human tissues. We describe a set of integrated experiments designed to investigate the effects of common genetic variability on DNA methylation, mRNA expression and microRNA (miRNA) expression in four distinct human brain regions. We show that brain tissues may be readily distinguished based on methylation status or expression profile. We find an abundance of genetic cis regulation mRNA expression and show for the first time abundant quantitative trait loci for DNA CpG methylation. We observe that the largest magnitude effects occur across distinct brain regions. We believe these data, which we have made publicly available, will be useful in understanding the biological effects of genetic variation. Authorized Access data: Mapping of GEO sample accessions to dbGaP subject/sample IDs is available through dbGaP Authorized Access, see http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000249.v1.p1 Because of our interest in genomic regulation of expression and neurological disorders we embarked upon a series of experiments to provide a brain region-specific contextual framework for genetic and epigenetic regulation of gene expression. We obtained frozen brain tissue from the cerebellum, frontal cortex, pons and temporal cortex from 150 subjects (total 600 tissue samples). We undertook four separate assays across this series; first, genome-wide SNP genotyping; second, assay of >27,000 CpG methylation sites in each of the four brain regions; third, mRNA expression profiling of >22,000 transcripts in all four brain regions; and, fourth, miRNA expression profiling of 735 miRNA transcripts. Here we discuss the results of these experiments, particularly in the context of integrated datasets to define expression and CpG methylation quantitative trait loci (eQTL and methQTL) and detailing differences and similarities across brain regions.

Dataset Information

Tumor Expression Quantitative Trait Methylation Screening Reveals Distinct CpG Panels for Deconvolving Cancer Immune Signatures.

Significance

Publications

Tumor Expression Quantitative Trait Methylation Screening Reveals Distinct CpG Panels for Deconvolving Cancer Immune Signatures.

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