Abstract
BackgroundMAP2K4 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.MethodsWe 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.ResultsIn 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.ConclusionsMAP2K4 is targeted by genetic inactivation in ovarian cancer and restricted to high grade serous and endometrioid carcinomas in our cohort.
Highlights
MAP2K4 is a putative tumor and metastasis suppressor gene frequently found to be deleted in various cancer types
We have previously reported that recurrent homozygous deletions appear to target MAP2K4 in primary ovarian tumors, and the gene lay in a minimal region of loss of heterozygosity (LOH) in 68% (72/106) of the cases, the second most frequent locus targeted by LOH [18]
In a recent copy number analysis [28] we found that 164/398 (41%) ovarian carcinomas of primarily serous/endometrioid subtype showed at least hemizygous copy number loss at MAP2K4
Summary
MAP2K4 is a putative tumor and metastasis suppressor gene frequently found to be deleted in various cancer types. The genetic evidence for a role of MAP2K4 in cancer is gathering strength It was initially described as a tumor suppressor gene (TSG), with a low frequency of deletions and mutations reported in a variety of cancer types [9]. In recent high-throughput sequencing and copy number studies, MAP2K4 appears to be only very rarely targeted by base pair level mutation but is consistently identified as a common target for deletion, including homozygous deletion [10,11,12] While some of these deletions may be a consequence of LOH targeting the nearby TP53 gene on 17q12, in a few instances there are homozygous deletions that appear to target only MAP2K4. In contrast, overexpression and silencing of the gene in a different cellular context was found to support a pro-oncogenic role for MAP2K4 [14]
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