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ACTN4 gene amplification and actinin‐4 protein overexpression drive tumour development and histological progression in a high‐grade subset of ovarian clear‐cell adenocarcinomas
Author(s) -
Yamamoto Sohei,
Tsuda Hitoshi,
Honda Kazufumi,
Takano Masashi,
Tamai Seiichi,
Imoto Issei,
Inazawa Johji,
Yamada Tesshi,
Matsubara Osamu
Publication year - 2012
Publication title -
histopathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.626
H-Index - 124
eISSN - 1365-2559
pISSN - 0309-0167
DOI - 10.1111/j.1365-2559.2011.04163.x
Subject(s) - microbiology and biotechnology , biology , immunohistochemistry , cancer research , histology , cell , pathology , medicine , immunology , genetics
Yamamoto S, Tsuda H, Honda K, Takano M, Tamai S, Imoto I, Inazawa J, Yamada T & Matsubara O
(2012) Histopathology 60, 1073–1083ACTN4 gene amplification and actinin‐4 protein overexpression drive tumour development and histological progression in a high‐grade subset of ovarian clear‐cell adenocarcinomas Aims: 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). Methods and 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. Conclusion: Accumulative genomic gains of ACTN4 , causing actinin‐4 protein overexpression, drive the development and progression of ovarian CCAs with high‐grade histology.