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Open Access Research article

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

Sally J Davis12, David YH Choong1, Manasa Ramakrishna12, Georgina L Ryland13, Ian G Campbell12 and Kylie L Gorringe12*

Author Affiliations

1 VBCRC Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, St. Andrew's Pl., East Melbourne, Victoria, Australia

2 Department of Pathology, University of Melbourne, Parkville, Victoria, Australia

3 Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia

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BMC Cancer 2011, 11:173  doi:10.1186/1471-2407-11-173

Published: 17 May 2011

Abstract

Background

MAP2K4 is a putative tumor and metastasis suppressor gene frequently found to be deleted in various cancer types. We aimed to conduct a comprehensive analysis of this gene to assess its involvement in ovarian cancer.

Methods

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.

Results

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.

Conclusions

MAP2K4 is targeted by genetic inactivation in ovarian cancer and restricted to high grade serous and endometrioid carcinomas in our cohort.