title: ASCL1-coexpression profiling but not single gene expression profiling defines lung adenocarcinomas of neuroendocrine nature with poor prognosis.
abstract: BACKGROUND
  Lung adenocarcinoma is heterogeneous regarding histology, etiology and prognosis. Although there have been several attempts to find a subgroup with poor prognosis, it is unclear whether or not adenocarcinoma with neuroendocrine (NE) nature has unfavorable prognosis.
  
  
  METHODS
  To elucidate whether a subtype of adenocarcinoma with NE nature has poor prognosis, we performed gene expression profiling by cDNA microarray for 262 Japanese lung cancer and 30 normal lung samples, including 171 adenocarcinomas, 56 squamous cell carcinomas and 35 NE tumors. A co-expression gene set with ASCL1, an NE master gene, was utilized to classify tumors by non-negative matrix factorization, followed by validation using an ASCL1 knock-down gene set in DMS79 cells as well as an independent cohort (n=139) derived from public microarray databases as a test set.
  
  
  RESULTS
  The co-expression gene set classified the adenocarcinomas into alveolar cell (AL), squamoid, and NE subtypes. The NE subtype, which clustered together almost all the NE tumors, had significantly poorer prognosis than the AL subtype that clustered with normal lung samples (p=0.0075). The knock-down gene set also classified the 171 adenocarcinomas into three subtypes and this NE subtype also had the poorest prognosis. The co-expression gene set classified the independent database-derived American cohort into two subtypes, with the NE subtype having poorer prognosis. None of the single NE gene expression was found to be linked to survival difference.
  
  
  CONCLUSIONS
  Co-expression gene set with ASCL1, rather than single NE gene expression, successfully identifies an NE subtype of lung adenocarcinoma with poor prognosis.
authors: Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo, Japan.
authors: Takeshi
authors: T
authors: Fujiwara
authors: Miyako
authors: M
authors: Hiramatsu
authors: Takayuki
authors: T
authors: Isagawa
authors: Hironori
authors: H
authors: Ninomiya
authors: Kentaro
authors: K
authors: Inamura
authors: Shumpei
authors: S
authors: Ishikawa
authors: Masaru
authors: M
authors: Ushijima
authors: Masaaki
authors: M
authors: Matsuura
authors: Michael H
authors: MH
authors: Jones
authors: Miyuki
authors: M
authors: Shimane
authors: Hitoshi
authors: H
authors: Nomura
authors: Yuichi
authors: Y
authors: Ishikawa
authors: Hiroyuki
authors: H
authors: Aburatani
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics*; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D015999:Multivariate Analysis; D055099:Neuroendocrine Cells / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D015996:Survival Rate
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D034741:RNA, Small Interfering; C065500:ASCL1 protein, human