Genome-wide analysis of DNA methylation and the gene expression change in lung cancer.
BACKGROUND
The recent DNA methylation studies on cancers have revealed the necessity of profiling an entire human genome and not to restrict the profiling to specific regions of the human genome. It has been suggested that genome-wide DNA methylation analysis enables us to identify the genes that are regulated by DNA methylation in carcinogenesis.


METHODS
So, we performed whole-genome DNA methylation analysis for human lung squamous cell carcinoma (SCC), which is strongly related with smoking. We also performed microarrays using 21 pairs of normal lung tissues and tumors from patients with SCC. By combining these data, 30 hypermethylated and down-regulated genes, and 22 hypomethylated and up-regulated genes were selected. The gene expression level and DNA methylation pattern were confirmed by semiquantitative reverse-transcriptase polymerase chain reaction and pyrosequencing, respectively.


RESULTS
By these validations, we selected five hypermethylated and down-regulated genes and one hypomethylated and up-regulated gene. Moreover, these six genes were proven to be actually regulated by DNA methylation by confirming the recovery of their DNA methylation pattern and gene expression level using a demethylating agent. The DNA methylation pattern of the CYTL1 promoter region was significantly different between early and advanced stages of SCC.


CONCLUSIONS
In conclusion, by combining the whole-genome DNA methylation pattern and the gene expression profile, we identified the six genes (CCDC37, CYTL1, CDO1, SLIT2, LMO3, and SERPINB5) that are regulated by DNA methylation, and we suggest their value as target molecules for further study of SCC.
Department of Translational Research, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
Yong-Jae
YJ
Kwon
Seog Joo
SJ
Lee
Jae Soo
JS
Koh
Sung Han
SH
Kim
Hae Won
HW
Lee
Moon Chul
MC
Kang
Jae Bum
JB
Bae
Young-Joon
YJ
Kim
Jong Ho
JH
Park
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001798:Blood Proteins / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D050558:Cysteine Dioxygenase / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D019175:DNA Methylation; D015536:Down-Regulation; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D060588:LIM Domain Proteins / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D009367:Neoplasm Staging; D009419:Nerve Tissue Proteins / Q000235:genetics; D015843:Serpins / Q000235:genetics; D015854:Up-Regulation; D000098552:Slit Homolog 2 Protein
D048868:Adaptor Proteins, Signal Transducing; D001798:Blood Proteins; C412483:CYTL1 protein, human; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C502335:LMO3 protein, human; D009419:Nerve Tissue Proteins; C085344:SERPIN-B5; D015843:Serpins; D050558:Cysteine Dioxygenase; D000098552:Slit Homolog 2 Protein