title: Actinin-4 gene amplification in ovarian cancer: a candidate oncogene associated with poor patient prognosis and tumor chemoresistance.
abstract: Actinin-4, an isoform of non-muscular alpha-actinin, enhances cell motility by bundling the actin cytoskeleton. We previously reported a prognostic implication of high immunohistochemical expression of actinin-4 protein in ovarian cancers. Chromosomal gain or amplification of the 19q12-q13 region has been reported in ovarian cancer. We hypothesized that the actinin-4 (ACTN4) gene might be a target of the 19q12-q13 amplicon and play an essential role of ovarian cancer progression. In total, 136 advanced-stage ovarian cancers were investigated for the copy number of the ACTN4 gene on chromosome 19q13, using fluorescence in situ hybridization, and the correlation of the ACTN4 copy number with actinin-4 protein immunoreactivity and major clinicopathological factors was investigated. A higher copy number (> or =4 copies) of the ACTN4 gene was detected in 29 (21%) cases and was highly associated with the intensity of actinin-4 immunoreactivity (P<0.0001), a high histological tumor grade (P=0.030), a clear-cell adenocarcinoma histology (P=0.012), resistance to first-line chemotherapies (P=0.028), and poor patient outcome (P=0.0011). Univariate analyses using the Cox regression model showed that a higher ACTN4 gene copy number was able to predict patient outcome more accurately than high actinin-4 immunoreactivity (relative risk: 2.48 vs 1.55). Multivariate analysis showed that a higher copy number of the ACTN4 gene and the degree of residual disease were independent prognostic factors for overall patient survival. The actinin-4 gene may be a target of the 19q amplicon, acting as a candidate oncogene, and serve as a predictor of poor outcome and tumor chemoresistance in patients with advanced-stage ovarian cancers.
authors.affiliation: Department of Basic Pathology, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Sohei
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tsuda
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Honda
authors.forename: Kaoru
authors.initials: K
authors.lastname: Onozato
authors.forename: Masashi
authors.initials: M
authors.lastname: Takano
authors.forename: Seiichi
authors.initials: S
authors.lastname: Tamai
authors.forename: Issei
authors.initials: I
authors.lastname: Imoto
authors.forename: Johji
authors.initials: J
authors.lastname: Inazawa
authors.forename: Tesshi
authors.initials: T
authors.lastname: Yamada
authors.forename: Osamu
authors.initials: O
authors.lastname: Matsubara
mesh_terms: D000185:Actinin / Q000096:biosynthesis / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D009857:Oncogenes; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D046888:Tissue Array Analysis
chemical_list: C111453:ACTN4 protein, human; D014408:Biomarkers, Tumor; D000185:Actinin