title: DNA repair biomarker profiling of head and neck cancer: Ku80 expression predicts locoregional failure and death following radiotherapy.
abstract: OBJECTIVE
  Radiotherapy plays an integral role in the treatment of head and neck squamous cell carcinoma (HNSCC). Although proteins involved in DNA repair may predict HNSCC response to radiotherapy, none has been validated in this context. We examined whether differential expression of double-strand DNA break (DSB) repair proteins in HNSCC, the chief mediators of DNA repair following irradiation, predict for treatment outcomes.
  
  
  METHODS
  Archival HNSCC tumor specimens (n = 89) were assembled onto a tissue microarray and stained with antibodies raised against 38 biomarkers. The biomarker set was enriched for proteins involved in DSB repair, in addition to established mechanistic markers of radioresistance. Staining was correlated with treatment response and survival alongside established clinical and pathologic covariates. Results were validated in an independent intramural cohort (n = 34).
  
  
  RESULTS
  Ku80, a key mediator of DSB repair, correlated most closely with clinical outcomes. Ku80 was overexpressed in half of all tumors, and its expression was independent of all other covariates examined. Ku80 overexpression was an independent predictor for both locoregional failure and mortality following radiotherapy (P < 0.01). The predictive power of Ku80 overexpression was confined largely to HPV-negative HNSCC, where it conferred a nine-fold greater risk of death at two years.
  
  
  CONCLUSIONS
  Ku80 overexpression is a common feature of HNSCC, and is a candidate DNA repair-related biomarker for radiation treatment failure and death, particularly in patients with high-risk HPV-negative disease. It is a promising, mechanistically rational biomarker to select individual HPV-negative HNSCC patients for strategies to intensify treatment.
authors.affiliation: Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Moeller
authors.forename: John S
authors.initials: JS
authors.lastname: Yordy
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Williams
authors.forename: Uma
authors.initials: U
authors.lastname: Giri
authors.forename: Uma
authors.initials: U
authors.lastname: Raju
authors.forename: David P
authors.initials: DP
authors.lastname: Molkentine
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Byers
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.forename: Michael D
authors.initials: MD
authors.lastname: Story
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.forename: Erich M
authors.initials: EM
authors.lastname: Sturgis
authors.forename: Randal S
authors.initials: RS
authors.lastname: Weber
authors.forename: Adam S
authors.initials: AS
authors.lastname: Garden
authors.forename: K Kian
authors.initials: KK
authors.lastname: Ang
authors.forename: David L
authors.initials: DL
authors.lastname: Schwartz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D052685:Alphapapillomavirus; D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy* / Q000821:virology; D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases / Q000378:metabolism*; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy* / Q000821:virology; D006801:Humans; D000072200:Ku Autoantigen; D008297:Male; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000150:complications; D040081:Protein Array Analysis; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D004265:DNA Helicases; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen; D045643:DNA Repair Enzymes