title: Distinct outcome of stage I lung adenocarcinoma with ACTN4 cell motility gene amplification.
abstract: BACKGROUND
  Even if detected at an early stage, a substantial number of lung cancers relapse after curative surgery. However, no method for distinguishing such tumors has yet been established.
  
  
  METHODS
  The copy number of the actinin-4 (ACTN4) gene was determined by fluorescence in situ hybridization on tissue microarrays comprising 543 surgically resected adenocarcinomas of the lung.
  
  
  RESULTS
  Amplification (an increase in the copy number by ≥ 2.0 fold) of the ACTN4 gene was detected in two of seven lung adenocarcinoma cell lines and 79 (15%) of 543 cases of pathological stage I-IV lung adenocarcinoma. Multivariate analysis revealed that ACTN4 gene amplification was the most significant independent factor associated with an extremely high risk of death (hazard ratio, 6.78; P = 9.48 × 10(-5), Cox regression analysis) among 290 patients with stage I lung adenocarcinoma. The prognostic significance of ACTN gene amplification was further validated in three independent cohorts totaling 1033 patients.
  
  
  CONCLUSIONS
  Amplification of the ACTN4 gene defines a small but substantial subset of patients with stage I lung adenocarcinoma showing a distinct outcome. Such patients require intensive medical attention and might benefit from postoperative adjuvant chemotherapy.
authors.affiliation: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo; Department of Internal Medicine, Division of Pulmonary Medicine, Infectious Diseases and Oncology, Nippon Medical School, Tokyo.
authors.forename: R
authors.initials: R
authors.lastname: Noro
authors.affiliation: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo.
authors.forename: K
authors.initials: K
authors.lastname: Honda
authors.affiliation: Pathology and Clinical Laboratory Division, National Cancer Center Hospital, Tokyo.
authors.forename: K
authors.initials: K
authors.lastname: Tsuta
authors.affiliation: Department of Pathology, Research Center for Innovative Oncology, National Cancer Center Research Institute, Tokyo.
authors.forename: G
authors.initials: G
authors.lastname: Ishii
authors.affiliation: Pathology and Clinical Laboratory Division, National Cancer Center Hospital, Tokyo.
authors.forename: A M
authors.initials: AM
authors.lastname: Maeshima
authors.affiliation: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo.
authors.forename: N
authors.initials: N
authors.lastname: Miura
authors.affiliation: Division of Clinical Laboratories, National Cancer Center Hospital, Tokyo.
authors.forename: K
authors.initials: K
authors.lastname: Furuta
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo.
authors.forename: T
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Pathology and Clinical Laboratory Division, National Cancer Center Hospital, Tokyo.
authors.forename: H
authors.initials: H
authors.lastname: Tsuda
authors.affiliation: Department of Pathology, Research Center for Innovative Oncology, National Cancer Center Research Institute, Tokyo.
authors.forename: A
authors.initials: A
authors.lastname: Ochiai
authors.affiliation: Mitsui Knowledge Industry, Tokyo.
authors.forename: T
authors.initials: T
authors.lastname: Sakuma
authors.affiliation: Department of Internal Medicine, Division of Pulmonary Medicine, Infectious Diseases and Oncology, Nippon Medical School, Tokyo.
authors.forename: N
authors.initials: N
authors.lastname: Nishijima
authors.affiliation: Department of Internal Medicine, Division of Pulmonary Medicine, Infectious Diseases and Oncology, Nippon Medical School, Tokyo.
authors.forename: A
authors.initials: A
authors.lastname: Gemma
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital, Tokyo.
authors.forename: H
authors.initials: H
authors.lastname: Asamura
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nagai
authors.affiliation: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo. Electronic address: tyamada@ncc.go.jp.
authors.forename: T
authors.initials: T
authors.lastname: Yamada
mesh_terms: D000185:Actinin / Q000235:genetics*; D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D000077192:Adenocarcinoma of Lung; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D013534:Survival; D046888:Tissue Array Analysis; D018631:ras Proteins / Q000235:genetics
chemical_list: C111453:ACTN4 protein, human; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D000185:Actinin; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: actinin-4 (ACTN4); biomarker; gene amplification; lung neoplasm; prognosis