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Integrative discovery of epigenetically derepressed cancer testis antigens in NSCLC
Chad A Glazer1, Ian M Smith, Michael F Ochs
1Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America.
Background:
Cancer/testis antigens (CTAs) were first discovered as immunogenic targets normally expressed in germline cells, but differentially expressed in a variety of human cancers. In this study, we used an integrative epigenetic screening approach to identify coordinately expressed genes in human non-small cell lung cancer (NSCLC) whose transcription is driven by promoter demethylation.
Methodology/Principal Findings:
Our screening approach found 290 significant genes from the over 47,000 transcripts incorporated in the Affymetrix Human Genome U133 Plus 2.0 expression array. Of the top 55 candidates, 10 showed both differential overexpression and promoter region hypomethylation in NSCLC. Surprisingly, 6 of the 10 genes discovered by this approach were CTAs. Using a separate cohort of primary tumor and normal tissue, we validated NSCLC promoter hypomethylation and increased expression by quantitative RT-PCR for all 10 genes. We noted significant, coordinated coexpression of multiple target genes, as well as coordinated promoter demethylation, in a large set of individual tumors that was associated with the SCC subtype of NSCLC. In addition, we identified 2 novel target genes that exhibited growth-promoting effects in multiple cell lines.
Conclusions/Significance:
Coordinated promoter demethylation in NSCLC is associated with aberrant expression of CTAs and potential, novel candidate protooncogenes that can be identified using integrative discovery techniques. These findings have significant implications for discovery of novel CTAs and CT antigen directed immunotherapy.
Insights
This study identifies novel cancer-testis antigens (CTAs) and proto-oncogenes in non-small cell lung cancer (NSCLC) through epigenetic screening. Aberrant CTA expression linked to promoter demethylation offers new immunotherapy targets.
Area of Science:
- Epigenetics
- Oncology
- Immunology
Background:
- Cancer/testis antigens (CTAs) are immunogenic targets found in germline cells and aberrantly expressed in various cancers.
- Non-small cell lung cancer (NSCLC) exhibits differential CTA expression, presenting potential therapeutic targets.
Purpose of the Study:
- To identify coordinately expressed genes in NSCLC driven by promoter demethylation using an integrative epigenetic screening approach.
- To discover novel CTAs and proto-oncogenes associated with aberrant gene expression in NSCLC.
Main Methods:
- Utilized an integrative epigenetic screening approach on Affymetrix Human Genome U133 Plus 2.0 arrays.
- Validated findings using quantitative RT-PCR on a separate cohort of primary NSCLC tumors and normal tissues.
- Analyzed gene coexpression and promoter demethylation patterns, correlating them with NSCLC subtypes.
Main Results:
- Identified 290 significant genes, with 10 showing differential overexpression and promoter hypomethylation in NSCLC.
- Discovered that 6 of these 10 genes were CTAs, with coordinated expression and demethylation observed in SCC subtype.
- Identified 2 novel genes with growth-promoting effects in NSCLC cell lines.
Conclusions:
- Coordinated promoter demethylation in NSCLC drives aberrant CTA expression and identifies novel proto-oncogene candidates.
- Findings highlight the utility of integrative discovery techniques for novel CTA identification.
- Results have significant implications for developing novel CTAs and CT antigen-directed immunotherapies for NSCLC.
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