title: The Histologic Classifications of Lung Adenocarcinomas Are Discriminable by Unique Lineage Backgrounds.
abstract: Lung adenocarcinomas are a heterogeneous set of diseases with distinct genetic and histologic characteristics. Besides the discovery of oncogenic mutations and introduction of the histologic classifications (2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society and 2015 WHO), increasing evidence has linked this intertumor heterogeneity to the lung lineage-specific pathways and lineage genes. Therefore, in this study, we assessed the gene expression of identified lung lineage genes to study their role in distinguishing lung adenocarcinoma diversities.
  
  
  
  A total of 278 surgically resected lung adenocarcinomas were included. Each case was evaluated for genetic mutations and histologic classification. Lineage genes associated with respiratory tract differentiation (NK2 homeobox 1 gene [NKX2-1], GATA protein binding 6 gene [GATA6], foxhead box J1 gene [FOXJ1], and SAM pointed domain containing ETS transcription factor gene [SPDEF]) and stem/basal-like status (inhibitor of DNA binding 2, HLH protein gene [ID2], POU class 5 homeobox 1 gene [POU5F1], SRY-box 2 gene [SOX2], and v-myc avian myelocytomatosis viral oncogene homolog gene [MYC]) were selected. mRNA expression of these genes in each tumor sample was assessed by quantitative real-time polymerase chain reaction and normalized to paired normal lung tissue.
  
  
  
  Distinct lineage gene expressions were found on the basis of genetic and histologic diversities. Expression of NKX2-1, GATA6, FOXJ1, and POU5F1 exhibited a significant linear relationship across histologic subgroups that was independent of genetic mutation status. Expression levels of NKX2-1 and POU5F1 were also associated with EGFR mutation status, independent of histologic subtypes. Further analysis revealed that the overexpression of SPDEF defined longer relapse-free survivals, especially in stage I disease.
  
  
  
  For the first time, we showed the unique lineage backgrounds of different histologic subtypes and oncogenic mutations. Assessing this added parameter might be beneficial in discriminating intertumor heterogeneity, advancing target exploration, developing theranostic/prognostic biomarkers, and designing clinical trials.
authors: Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors: Haichuan
authors: H
authors: Hu
authors: Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors: Zhengliang
authors: Z
authors: Sun
authors: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors: Yuan
authors: Y
authors: Li
authors: Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors: Yiliang
authors: Y
authors: Zhang
authors: Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors: Hang
authors: H
authors: Li
authors: Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors: Yang
authors: Y
authors: Zhang
authors: Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors: Yunjian
authors: Y
authors: Pan
authors: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors: Lei
authors: L
authors: Shen
authors: Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China.
authors: Rui
authors: R
authors: Wang
authors: Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors: Yihua
authors: Y
authors: Sun
authors: Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China; Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China. Electronic address: hqchen1@yahoo.com.
authors: Haiquan
authors: H
authors: Chen
mesh_terms: D000230:Adenocarcinoma / Q000145:classification* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D006801:Humans; D008175:Lung Neoplasms / Q000145:classification* / Q000473:pathology
keywords: Histologic classifications; Lineage gene; Lung adenocarcinomas; Tumor diversity