title: ACTN4 gene amplification and actinin-4 protein overexpression drive tumour development and histological progression in a high-grade subset of ovarian clear-cell adenocarcinomas.
abstract: OBJECTIVE
  Actinin-4, encoded by the ACTN4 gene located on chromosome 19q13.2, enhances cell motility by bundling the actin cytoskeleton. We assessed how ACTN4/actinin-4 alterations contribute to the tumorigenesis of ovarian clear-cell adenocarcinomas (CCAs).
  
  
  RESULTS
  Fluorescence in-situ hybridization analysis demonstrated that ACTN4 amplification (≥4 ACTN4 copies in ≥40% of cells) occurred in 27 (33%) of 81 CCAs and genomic gains of ACTN4 were associated strongly with immunohistochemical actinin-4 overexpression, poorly differentiated tumour histology and shorter patient survival (all P < 0.05). From the 27 ACTN4-amplified CCAs, 23 tumours with adjacent putative precursor lesions were selected and examined for ACTN4/actinin-4 alterations with respect to their intratumoral heterogeneity. In this selected cohort, none of the precursors lacking cytological atypia exhibited gains of ACTN4 or actinin-4 overexpression; 50% of the atypical endometrioses and 75% of the borderline CCAFs showed low-level gains of ACTN4 and actinin-4 overexpression, respectively. In 12 of 23 ACTN4-amplified CCAs, intratumoral heterogeneity for ACTN4 alterations was documented in carcinomatous components; the better differentiated carcinoma components exhibited fewer alterations than those with poorly differentiated histology.
  
  
  CONCLUSIONS
  Accumulative genomic gains of ACTN4, causing actinin-4 protein overexpression, drive the development and progression of ovarian CCAs with high-grade histology.
authors.affiliation: Department of Basic Pathology, National Defense Medical College, Saitama, Japan. dr21001@ndmc.ac.jp
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: 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 / Q000235:genetics* / Q000378:metabolism*; D018262:Adenocarcinoma, Clear Cell / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000232:Adenofibroma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D018450:Disease Progression; D004715:Endometriosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D010051:Ovarian Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation
chemical_list: C111453:ACTN4 protein, human; D000185:Actinin