Analysis of the Mitogen-activated protein kinase kinase 4 (MAP2K4) tumor suppressor gene in ovarian cancer

We screened for mutations in MAP2K4 using High Resolution Melt analysis of 149 primary ovarian tumors and methylation at the promoter using Methylation-Specific Single-Stranded Conformation Polymorphism analysis of 39 tumors. We also considered the clinical impact of changes in MAP2K4 using publicly available expression and copy number array data. Finally, we used siRNA to measure the effect of reducing MAP2K4 expression in cell lines.In addition to 4 previously detected homozygous deletions, we identified a homozygous 16 bp truncating deletion and a heterozygous 4 bp deletion, each in one ovarian tumor. No promoter methylation was detected. The frequency of MAP2K4 homozygous inactivation was 5.6% overall, and 9.8% in high-grade serous cases. Hemizygous deletion of MAP2K4 was observed in 38% of samples. There were significant correlations of copy number and expression in three microarray data sets. There was a significant correlation between MAP2K4 expression and overall survival in one expression array data set, but this was not confirmed in an independent set. Treatment of JAM and HOSE6.3 cell lines with MAP2K4 siRNA showed some reduction in proliferation.MAP2K4 is targeted by genetic inactivation in ovarian cancer and restricted to high grade serous and endometrioid carcinomas in our cohort.Mitogen-activated protein kinase kinase 4 (MAP2K4) is a gene encoding a member of the MAP kinase signalling family [1,2]. This 399 amino acid protein is a component of a triple kinase cascade whereby activated MAP kinases are successively phosphorylated to mediate cellular responses to cytokine signals, stress and other extracellular stimuli [3]. The phosphorylation cascade is initiated by the activation of MAP3K proteins, such as MEKK and MLK, which phosphorylate MAP2K4. In its activated state, MAP2K4 can phosphorylate JNK or p38 with dual specificity, resulting in the activation of the stress activated protein kinase (SAPK) pathway, which has been associated with apoptosis a