title: Analysis of the mitogen-activated protein kinase kinase 4 (MAP2K4) tumor suppressor gene in ovarian cancer.
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.
authors.affiliation: VBCRC Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Sally J
authors.initials: SJ
authors.lastname: Davis
authors.forename: David Y H
authors.initials: DY
authors.lastname: Choong
authors.forename: Manasa
authors.initials: M
authors.lastname: Ramakrishna
authors.forename: Georgina L
authors.initials: GL
authors.lastname: Ryland
authors.forename: Ian G
authors.initials: IG
authors.lastname: Campbell
authors.forename: Kylie L
authors.initials: KL
authors.lastname: Gorringe
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D049109:Cell Proliferation; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D055785:Gene Knockdown Techniques; D005838:Genotype; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000401:mortality; D011401:Promoter Regions, Genetic / Q000235:genetics; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D025521:Tumor Suppressor Proteins; D048670:MAP Kinase Kinase 4