A functional copy-number variation in MAPKAPK2 predicts risk and prognosis of lung cancer

Abstract

Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) may promote cancer development and progression by inducing tumorigenesis and drug resistance. To assess whether the copy-number variation g.CNV-30450 located in the MAPKAPK2 promoter has any effect on lung cancer risk or prognosis, we investigated the association between g.CNV-30450 and cancer risk in three independent case-control studies of 2,332 individuals with lung cancer and 2,457 controls and the effects of g.CNV-30450 on cancer prognosis in 1,137 individuals with lung cancer with survival data in southern and eastern Chinese populations. We found that those subjects who had four copies of g.CNV-30450 had an increased cancer risk (odds ratio = 1.94, 95% confidence interval [CI] = 1.61-2.35) and a worse prognosis for individuals with lung cancer (with a median survival time of only 9 months) (hazard ratio = 1.47, 95% CI = 1.22-1.78) compared with those with two or three copies (with a median survival time of 14 months). Meanwhile, four copies of g.CNV-30450 significantly increased MAPKAPK2 expression, both in vitro and in vivo, compared with two or three copies. Our study establishes a robust association between the functional g.CNV-30450 in MAPKAPK2 and risk as well as prognosis of lung cancer, and it presents this functional copy-number variation as a potential biomarker for susceptibility to and prognosis for lung cancer.

Figure 1

Kaplan-Meier Survival Curve for Individuals with Lung Cancer by MAPKAPK2 g.CNV-30450 Genotype (A) The discovery set. (B) The validation set I. (C) The validation set II.

Figure 2

Functional Analysis of MAPKAPK2 g.CNV-30450 In Vivo and In Vitro (A) Schematic of the two reporter-gene constructs containing the single or dual g.CNV-30450. (B) Luciferase expression of the two constructs in lung cells (16HBE, A549, and NCI-520). Student’s t test was used to test the differences in the expression levels of different constructs. (C) The relative mRNA level of MAPKAPK2 by g.CNV-30450 genotype. (D) The MAPKAPK2 and β-actin protein band in lung cancer tissues. (E) MAPKAPK2 expressions by g.CNV-30450 genotype. Columns, mean from three independent experiments; bars, SD. The copy number of g.CNV-30450 was from blood DNA. The dual copies of g.CNV-30450 had significantly higher luciferase activity than the single copy; thus, the four copies of MAPKAPK2 g.CNV-30450 had significantly increased expressions (mean ± SD) compared with the two or three copies.