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Integrative discovery of epigenetically derepressed cancer testis antigens in NSCLC

Glazer, CA and Smith, IM and Ochs, MF and Begum, S and Westra, W and Chang, SS and Sun, W and Bhan, S and Khan, Z and Ahrendt, S and Califano, JA (2009) Integrative discovery of epigenetically derepressed cancer testis antigens in NSCLC. PLoS ONE, 4 (12).

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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. © 2009 Glazer et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Glazer, CA
Smith, IM
Ochs, MF
Begum, S
Westra, W
Chang, SS
Sun, W
Bhan, S
Khan, Z
Ahrendt, Ssaa39@pitt.eduSAA39
Califano, JA
ContributionContributors NameEmailPitt UsernameORCID
Date: 1 December 2009
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 4
Number: 12
DOI or Unique Handle: 10.1371/journal.pone.0008189
Refereed: Yes
MeSH Headings: Antigens, Neoplasm--genetics; Carcinoma, Non-Small-Cell Lung--genetics; Cell Line, Tumor; Cell Proliferation; DNA Methylation--genetics; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genes, Neoplasm--genetics; Genetic Testing--methods; Humans; Lung Neoplasms--genetics; Promoter Regions, Genetic--genetics
Other ID: NLM PMC2781168
PubMed Central ID: PMC2781168
PubMed ID: 19997593
Date Deposited: 03 Aug 2012 18:34
Last Modified: 25 Jan 2019 23:55


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