title: Lung squamous cell carcinomas with basaloid histology represent a specific molecular entity.
abstract: OBJECTIVE
  The basaloid carcinoma (pure) and the (mixed) basaloid variant of lung squamous cell carcinoma (SCC) have a dismal prognosis but their underlying specific molecular characteristics remain obscure and no therapy has proven to be efficient.
  
  
  METHODS
  To assess their molecular specificity among other lung SCCs we analyzed DNA copy number aberrations and mRNA expression pangenomic profiles of 93 SCCs, including 42 basaloid samples (24 pure, 18 mixed).
  
  
  RESULTS
  Supervised analyses reveal that pure basaloid tumors display a specific mRNA expression profile, encoding factors controlling the cell cycle, transcription, chromatin, and splicing, with prevalent expression in germline and stem cells, while genes related to squamous differentiation are underexpressed. From this signature, we derived a 2-genes (SOX4, IVL) immunohistochemistry-based predictor that discriminated basaloid tumors (pure and mixed) from non-basaloid tumors with 94% accuracy in an independent series. The pure basaloid tumors are also distinguished through unsupervised analyses. Using a centroid-based predictor, the corresponding molecular subtype was found in 8 independent public datasets (n = 58/533), and was shown to be associated with a very poor survival as compared with other SCCs (adjusted HR = 2.45; P = 0.000001).
  
  
  CONCLUSIONS
  This study enlightens the heterogeneity of SCCs that can be subclassified in mRNA expression subtypes. This study demonstrates for the first time that basaloid SCCs constitute a distinct histomolecular entity, which justifies its recognition and distinction from non-basaloid SCCs. In addition, their characteristic molecular profile highlights their intrinsic resistance to cytotoxic chemotherapy and could serve as a guide for targeted therapies.
authors.affiliation: Clinique de Pneumologie, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, INSERM U823, Université Joseph Fourrier, Grenoble, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Brambilla
authors.affiliation: Cartes d'Identité des Tumeurs (CIT) Program, Ligue Nationale Contre le Cancer, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Laffaire
authors.affiliation: Département d'Anatomie et Cytologie Pathologique, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, INSERM U823, Université Joseph Fourrier, Grenoble, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lantuejoul
authors.affiliation: Clinique de Pneumologie, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, INSERM U823, Université Joseph Fourrier, Grenoble, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Moro-Sibilot
authors.affiliation: Clinique de Pneumologie, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, INSERM U823, Université Joseph Fourrier, Grenoble, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Mignotte
authors.affiliation: Clinique de Pneumologie, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, INSERM U823, Université Joseph Fourrier, Grenoble, France.
authors.forename: François
authors.initials: F
authors.lastname: Arbib
authors.affiliation: Clinique de Pneumologie, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, INSERM U823, Université Joseph Fourrier, Grenoble, France.
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Toffart
authors.affiliation: Cartes d'Identité des Tumeurs (CIT) Program, Ligue Nationale Contre le Cancer, Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Petel
authors.affiliation: International Prevention Research Institute, Lyon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
authors.affiliation: INSERM, U823, Université Joseph Fourier, Institut Albert Bonniot, Grenoble, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Rousseaux
authors.affiliation: INSERM, U823, Université Joseph Fourier, Institut Albert Bonniot, Grenoble, France.
authors.forename: Saadi
authors.initials: S
authors.lastname: Khochbin
authors.affiliation: Cartes d'Identité des Tumeurs (CIT) Program, Ligue Nationale Contre le Cancer, Paris, France. ReyniesA@ligue-cancer.net EBrambilla@chu-grenoble.fr.
authors.forename: Aurélien
authors.initials: A
authors.lastname: de Reyniès
authors.affiliation: Département d'Anatomie et Cytologie Pathologique, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, INSERM U823, Université Joseph Fourrier, Grenoble, France. ReyniesA@ligue-cancer.net EBrambilla@chu-grenoble.fr.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D002869:Chromosome Aberrations; D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D012333:RNA, Messenger