title: Integrative discovery of epigenetically derepressed cancer testis antigens in NSCLC.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Glazer
authors.forename: Ian M
authors.initials: IM
authors.lastname: Smith
authors.forename: Michael F
authors.initials: MF
authors.lastname: Ochs
authors.forename: Shahnaz
authors.initials: S
authors.lastname: Begum
authors.forename: William
authors.initials: W
authors.lastname: Westra
authors.forename: Steven S
authors.initials: SS
authors.lastname: Chang
authors.forename: Wenyue
authors.initials: W
authors.lastname: Sun
authors.forename: Sheetal
authors.initials: S
authors.lastname: Bhan
authors.forename: Zubair
authors.initials: Z
authors.lastname: Khan
authors.forename: Steven
authors.initials: S
authors.lastname: Ahrendt
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Califano
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm