title: Validation of a gene expression signature for assessment of lymph node metastasis in oral squamous cell carcinoma.
abstract: OBJECTIVE
  Current assessment of lymph node metastasis in patients with head and neck squamous cell carcinoma is not accurate enough to prevent overtreatment. The aim of this study was validation of a gene expression signature for distinguishing metastasizing (N+) from nonmetastasizing (N0) squamous cell carcinoma of the oral cavity (OSCC) and oropharynx (OPSCC) in a large multicenter cohort, using a diagnostic DNA microarray in a Clinical Laboratory Improvement Amendments/International Organization for Standardization-approved laboratory.
  
  
  METHODS
  A multigene signature, previously reported as predictive for the presence of lymph node metastases in OSCC and OPSCC, was first re-evaluated and trained on 94 samples using generic, whole-genome, DNA microarrays. Signature genes were then transferred to a dedicated diagnostic microarray using the same technology platform. Additional samples (n=222) were collected from all head and neck oncologic centers in the Netherlands and analyzed with the diagnostic microarray. Human papillomavirus status was determined by real-time quantitative polymerase chain reaction.
  
  
  RESULTS
  The negative predictive value (NPV) of the diagnostic signature on the entire validation cohort (n=222) was 72%. The signature performed well on the most relevant subset of early-stage (cT1-T2N0) OSCC (n=101), with an NPV of 89%.
  
  
  CONCLUSIONS
  Combining current clinical assessment with the expression signature would decrease the rate of undetected nodal metastases from 28% to 11% in early-stage OSCC. This should be sufficient to enable clinicians to refrain from elective neck treatment. A new clinical decision model that incorporates the expression signature is therefore proposed for testing in a prospective study, which could substantially improve treatment for this group of patients.
authors.affiliation: Molecular Cancer Research, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, the Netherlands.
authors.forename: Sander R
authors.initials: SR
authors.lastname: van Hooff
authors.forename: Frank K J
authors.initials: FK
authors.lastname: Leusink
authors.forename: Paul
authors.initials: P
authors.lastname: Roepman
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Baatenburg de Jong
authors.forename: Ernst-Jan M
authors.initials: EJ
authors.lastname: Speel
authors.forename: Michiel W M
authors.initials: MW
authors.lastname: van den Brekel
authors.forename: Marie-Louise F
authors.initials: ML
authors.lastname: van Velthuysen
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
authors.forename: Robert J J
authors.initials: RJ
authors.lastname: van Es
authors.forename: Matthias A W
authors.initials: MA
authors.lastname: Merkx
authors.forename: J Alain
authors.initials: JA
authors.lastname: Kummer
authors.forename: C René
authors.initials: CR
authors.lastname: Leemans
authors.forename: Ed
authors.initials: E
authors.lastname: Schuuring
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Langendijk
authors.forename: Martin
authors.initials: M
authors.lastname: Lacko
authors.forename: Maria J
authors.initials: MJ
authors.lastname: De Herdt
authors.forename: Jeroen C
authors.initials: JC
authors.lastname: Jansen
authors.forename: Ruud H
authors.initials: RH
authors.lastname: Brakenhoff
authors.forename: Piet J
authors.initials: PJ
authors.lastname: Slootweg
authors.forename: Robert P
authors.initials: RP
authors.lastname: Takes
authors.forename: Frank C P
authors.initials: FC
authors.lastname: Holstege
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D015203:Reproducibility of Results; D059467:Transcriptome