title: Genomic aberrations in lung adenocarcinoma in never smokers.
abstract: BACKGROUND
  Lung cancer in never smokers would rank as the seventh most common cause of cancer death worldwide.
  
  
  RESULTS
  We performed high-resolution array comparative genomic hybridization analysis of lung adenocarcinoma in sixty never smokers and identified fourteen new minimal common regions (MCR) of gain or loss, of which five contained a single gene (MOCS2, NSUN3, KHDRBS2, SNTG1 and ST18). One larger MCR of gain contained NSD1. One focal amplification and nine gains contained FUS. NSD1 and FUS are oncogenes hitherto not known to be associated with lung cancer. FISH showed that the amplicon containing FUS was joined to the next telomeric amplicon at 16p11.2. FUS was over-expressed in 10 tumors with gain of 16p11.2 compared to 30 tumors without that gain. Other cancer genes present in aberrations included ARNT, BCL9, CDK4, CDKN2B, EGFR, ERBB2, MDM2, MDM4, MET, MYC and KRAS. Unsupervised hierarchical clustering with adjustment for false-discovery rate revealed clusters differing by the level and pattern of aberrations and displaying particular tumor characteristics. One cluster was strongly associated with gain of MYC. Another cluster was characterized by extensive losses containing tumor suppressor genes of which RB1 and WRN. Tumors in that cluster frequently harbored a central scar-like fibrosis. A third cluster was associated with gains on 7p and 7q, containing ETV1 and BRAF, and displayed the highest rate of EGFR mutations. SNP array analysis validated copy-number aberrations and revealed that RB1 and WRN were altered by recurrent copy-neutral loss of heterozygosity.
  
  
  CONCLUSIONS
  The present study has uncovered new aberrations containing cancer genes. The oncogene FUS is a candidate gene in the 16p region that is frequently gained in never smokers. Multiple genetic pathways defined by gains of MYC, deletions of RB1 and WRN or gains on 7p and 7q are involved in lung adenocarcinoma in never smokers.
authors.affiliation: Plate-forme de Biologie intégrée, Institut de recherche intégrée en Cancérologie à Villejuif, Villejuif, France.
authors.forename: Bastien
authors.initials: B
authors.lastname: Job
authors.forename: Alain
authors.initials: A
authors.lastname: Bernheim
authors.forename: Michèle
authors.initials: M
authors.lastname: Beau-Faller
authors.forename: Sophie
authors.initials: S
authors.lastname: Camilleri-Broët
authors.forename: Philippe
authors.initials: P
authors.lastname: Girard
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
authors.forename: Julien
authors.initials: J
authors.lastname: Mazières
authors.forename: Saloua
authors.initials: S
authors.lastname: Toujani
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lacroix
authors.forename: Julien
authors.initials: J
authors.lastname: Laffaire
authors.forename: Philippe
authors.initials: P
authors.lastname: Dessen
authors.forename: Pierre
authors.initials: P
authors.lastname: Fouret
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000368:Aged; D002869:Chromosome Aberrations; D004273:DNA, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D052138:Genes, Neoplasm; D020022:Genetic Predisposition to Disease; D023281:Genomics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D005810:Multigene Family; D012907:Smoking
chemical_list: D004273:DNA, Neoplasm; D066246:ErbB Receptors