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10.1245/s10434-006-9310-7
Annals of Surgical Oncology 14:2636-2642 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Aberrant Methylation of IL-12Rß2 Gene in Lung Adenocarcinoma Cells Is Associated with Unfavorable Prognosis

Makoto Suzuki, MD1, Toshihiko Iizasa, MD1, Takahiro Nakajima, MD1, Rieko Kubo, PhD1, Akira Iyoda, MD1, Kenzo Hiroshima, MD2, Yukio Nakatani, MD2 and Takehiko Fujisawa, MD1

1 Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
2 Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan

Correspondence: Address correspondence and reprint requests to: Takehiko Fujisawa, MD; E-mail: fujisawat{at}faculty.chiba-u.jp

Background: Interleukin-12 receptor ß 2(IL-12Rß 2) knock-out mice develop lung adeno-carcinoma, 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-12Rß 2 methylation is a common feature in human lung cancer.

Methods: We examined mRNA expression of IL-12Rß 2 in lung cancer cell lines, and normal bronchial, and tracheal epithelial cells using RT-PCR, and we examined the methylation status of IL-12Rß 2 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-12Rß 2 gene was reversely concordant with its mRNA expression. IL-12Rß 2 methylation was detected in 96 of 230 primary NSCLCs (42%) and 3 of 6 primary SCLCs (50%). IL-12Rß 2 methylation correlated with poorer prognosis in lung adenocarcinomas (hazard ratio = 2.33, P = 0.0059).

Conclusions: We conclude that epigenetic silencing of IL-12Rß 2 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.

Key Words: IL-12Rß2 • Methylation • Lung cancer • Prognosis






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