title: Diagnostic and prognostic significance of the alternatively spliced ACTN4 variant in high-grade neuroendocrine pulmonary tumours.
abstract: BACKGROUND
  High-grade neuroendocrine tumours (HGNTs) of the lung manifest a wide spectrum of clinical behaviour, but no method for predicting their outcome has been established.
  
  
  METHODS
  We newly established a monoclonal antibody specifically recognizing the product of the alternatively spliced ACTN4 transcript (namely, variant actinin-4), and used it to examine the expression of variant actinin-4 immunohistochemically in a total of 609 surgical specimens of various histological subtypes of lung cancer.
  
  
  RESULTS
  Variant actinin-4 was expressed in 55% (96/176) of HGNTs, but in only 0.8% (3/378) of non-neuroendocrine (NE) lung cancers. The expression of variant actinin-4 was significantly associated with poorer overall survival in HGNT patients (P=0.00021, log-rank test). Multivariate analysis using the Cox proportional hazards model showed that the expression of variant actinin-4 was the most significant independent negative predictor of survival in HGNT patients (hazard ratio (HR), 2.15; P=0.00113) after the presence of lymph node metastasis (HR, 2.25; P=0.00023).
  
  
  CONCLUSIONS
  The expression of variant actinin-4 is an independent prognostic factor for patients with HGNTs. This protein has a high affinity for filamentous actin polymers and likely promotes aggressive behaviour of cancer cells. The present clinical findings clearly support this notion.
authors.affiliation: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Miyanaga
authors.forename: K
authors.initials: K
authors.lastname: Honda
authors.forename: K
authors.initials: K
authors.lastname: Tsuta
authors.forename: M
authors.initials: M
authors.lastname: Masuda
authors.forename: U
authors.initials: U
authors.lastname: Yamaguchi
authors.forename: G
authors.initials: G
authors.lastname: Fujii
authors.forename: A
authors.initials: A
authors.lastname: Miyamoto
authors.forename: S
authors.initials: S
authors.lastname: Shinagawa
authors.forename: N
authors.initials: N
authors.lastname: Miura
authors.forename: H
authors.initials: H
authors.lastname: Tsuda
authors.forename: T
authors.initials: T
authors.lastname: Sakuma
authors.forename: H
authors.initials: H
authors.lastname: Asamura
authors.forename: A
authors.initials: A
authors.lastname: Gemma
authors.forename: T
authors.initials: T
authors.lastname: Yamada
mesh_terms: D000185:Actinin / Q000235:genetics*; D000368:Aged; D017398:Alternative Splicing; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000235:genetics*; D011379:Prognosis; D016016:Proportional Hazards Models
chemical_list: C111453:ACTN4 protein, human; D000185:Actinin