Integrative discovery of epigenetically derepressed cancer testis antigens in NSCLC.
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.
Glazer
Chad A
CA
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America.
Smith
Ian M
IM
Ochs
Michael F
MF
Begum
Shahnaz
S
Westra
William
W
Chang
Steven S
SS
Sun
Wenyue
W
Bhan
Sheetal
S
Khan
Zubair
Z
Ahrendt
Steven
S
Califano
Joseph A
JA
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
D000951:Antigens, Neoplasm