title: Molecular Characteristics of ERCC1-Negative versus ERCC1-Positive Tumors in Resected NSCLC.
abstract: OBJECTIVE
  Excision repair cross-complementation group 1 (ERCC1) is a protein involved in repair of DNA platinum adducts and stalled DNA replication forks. We and others have previously shown the influence of ERCC1 expression upon survival rates and benefit of cisplatin-based chemotherapy in patients with resected non-small-cell lung cancer (NSCLC). However, little is known about the molecular characteristics of ERCC1-positive and ERCC1-negative tumors.
  
  
  METHODS
  We took advantage of a cohort of 91 patients with resected NSCLC, for which we had matched frozen and paraffin-embedded samples to explore the comparative molecular portraits of ERCC1-positive and ERCC1-negative tumors of NSCLC. We carried out a global molecular analysis including assessment of ERCC1 expression levels by using both immunohistochemistry (IHC) and quantitative reverse transcriptase PCR (qRT-PCR), genomic instability, global gene and miRNA expression, and sequencing of selected key genes involved in lung carcinogenesis.
  
  
  RESULTS
  ERCC1 protein and mRNA expression were significantly correlated. However, we observed several cases with clear discrepancies. We noted that ERCC1-negative tumors had a higher rate of genomic abnormalities versus ERCC1-positive tumors. ERCC1-positive tumors seemed to share a common DNA damage response (DDR) phenotype with the overexpression of seven genes linked to DDR. The miRNA expression analysis identified miR-375 as significantly underexpressed in ERCC1-positive tumors.
  
  
  CONCLUSIONS
  Our data show inconsistencies in ERCC1 expression between IHC and qRT-PCR readouts. Furthermore, ERCC1 status is not linked to specific mutational patterns or frequencies. Finally, ERCC1-negative tumors have a high rate of genomic aberrations that could consequently influence prognosis in patients with resected NSCLC.
authors.affiliation: INSERM, U981; Institut de cancérologie Gustave Roussy (IGR), Villejuif, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Friboulet
authors.forename: Daniel
authors.initials: D
authors.lastname: Barrios-Gonzales
authors.forename: Frédéric
authors.initials: F
authors.lastname: Commo
authors.forename: Ken André
authors.initials: KA
authors.lastname: Olaussen
authors.forename: Stephan
authors.initials: S
authors.lastname: Vagner
authors.forename: Julien
authors.initials: J
authors.lastname: Adam
authors.forename: Aïcha
authors.initials: A
authors.lastname: Goubar
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dorvault
authors.forename: Vladimir
authors.initials: V
authors.lastname: Lazar
authors.forename: Bastien
authors.initials: B
authors.lastname: Job
authors.forename: Benjamin
authors.initials: B
authors.lastname: Besse
authors.forename: Pierre
authors.initials: P
authors.lastname: Validire
authors.forename: Philippe
authors.initials: P
authors.lastname: Girard
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lacroix
authors.forename: Johanna
authors.initials: J
authors.lastname: Hasmats
authors.forename: Fabienne
authors.initials: F
authors.lastname: Dufour
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004720:Endonucleases / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015996:Survival Rate
chemical_list: D004268:DNA-Binding Proteins; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C071447:ERCC1 protein, human; D004720:Endonucleases