title: Two prognostically significant subtypes of high-grade lung neuroendocrine tumours independent of small-cell and large-cell neuroendocrine carcinomas identified by gene expression profiles.
abstract: BACKGROUND
  Classification of high-grade neuroendocrine tumours (HGNT) of the lung currently recognises large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung carcinoma (SCLC) as distinct groups. However, a similarity in histology for these two carcinomas and uncertain clinical course have led to suggestions that a single HGNT classification would be more appropriate. Gene expression profiling, which can reproduce histopathological classification, and often defines new subclasses with prognostic significance, can be used to resolve HGNT classification.
  
  
  METHODS
  We used cDNA microarrays with 40?386 elements to analyse the gene expression profiles of 38 surgically resected samples of lung neuroendocrine tumours and 11 SCLC cell lines. Samples of large-cell carcinoma, adenocarcinoma, and normal lung were also included to give a total of 105 samples analysed. The data were subjected to filtering to yield informative genes before unsupervised hierarchical clustering that identified relatedness of tumour samples.
  
  
  RESULTS
  Distinct groups for carcinoids, large-cell carcinoma, adenocarcinoma, and normal lung were readily identified. However, we were unable to distinguish LCNEC from SCLC by gene expression profiling. Three independent rounds of unsupervised hierarchical clustering consistently divided SCLC samples into two main groups with LCNEC samples largely integrated with these groups. Furthermore, patients in one of the groups identified by clustering had a significantly better clinical outcome than the other (83% vs 12% survived for 5 years; p=0.0094. None of the highly proliferative SCLC cell lines subsequently analysed clustered with this good-prognosis group.
  
  
  CONCLUSIONS
  Our findings show that HGNT of the lung can be classified into two groups independent of SCLC and LCNEC. To this end, we have identified many genes, some of which encode well-characterised markers of cancer that distinguish the HGNT groups. These results have implications for the diagnosis, classification, and treatment of lung neuroendocrine tumours, and provide important insights into their underlying biology.
authors.affiliation: Chugai Pharmaceuticals c/o Proliferation Signal Division, University of Tokyo, Tokyo, Japan.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Jones
authors.forename: Carl
authors.initials: C
authors.lastname: Virtanen
authors.forename: Daisuke
authors.initials: D
authors.lastname: Honjoh
authors.forename: Tatsu
authors.initials: T
authors.lastname: Miyoshi
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Satoh
authors.forename: Sakae
authors.initials: S
authors.lastname: Okumura
authors.forename: Ken
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nomura
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ishikawa
mesh_terms: D014408:Biomarkers, Tumor; D018287:Carcinoma, Large Cell / Q000145:classification / Q000175:diagnosis / Q000235:genetics; D018278:Carcinoma, Neuroendocrine / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D018288:Carcinoma, Small Cell / Q000145:classification / Q000175:diagnosis / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods / Q000706:statistics & numerical data*; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers; D006801:Humans; D008175:Lung Neoplasms / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods / Q000706:statistics & numerical data*; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D005819:Genetic Markers