Aberrant methylation of IL-12Rbeta2 gene in lung adenocarcinoma cells is associated with unfavorable prognosis.
BACKGROUND
Interleukin-12 receptor beta2 (IL-12Rbeta2) knock-out mice develop lung adenocarcinoma, and epigenetic silencing by CpG methylation leads to loss of this gene in B-cell malignancies. The aim of this study was to determine whether IL-12Rbeta2 methylation is a common feature in human lung cancer.


METHODS
We examined mRNA expression of IL-12Rbeta2 in lung cancer cell lines, and normal bronchial, and tracheal epithelial cells using RT-PCR, and we examined the methylation status of IL-12Rbeta2 in primary lung cancers.


RESULTS
Loss of expression was found in 10 of 13 (77%) NSCLC cell lines, and 2 of 5 (40%) SCLC cell lines compared with normal bronchial or tracheal cells. Treatment of 11 expression-negative cell lines with a demethylating agent restored expression in all cases. Aberrant methylation status of IL-12Rbeta2 gene was reversely concordant with its mRNA expression. IL-12Rbeta2 methylation was detected in 96 of 230 primary NSCLCs (42%) and 3 of 6 primary SCLCs (50%). IL-12Rbeta2 methylation correlated with poorer prognosis in lung adenocarcinomas (hazard ratio = 2.33, P = 0.0059).


CONCLUSIONS
We conclude that epigenetic silencing of IL-12Rbeta2 is a frequent event in lung cancers. Aberrant methylation of this gene seems to be a useful predictor of long-term outcome for adenocarcinoma of the lung.
Suzuki
Makoto
M
Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Iizasa
Toshihiko
T
Nakajima
Takahiro
T
Kubo
Rieko
R
Iyoda
Akira
A
Hiroshima
Kenzo
K
Nakatani
Yukio
Y
Fujisawa
Takehiko
T
D000230:Adenocarcinoma / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics*; D011379:Prognosis; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D014407:Tumor Cells, Cultured
D018664:Interleukin-12