DNA repair biomarker profiling of head and neck cancer

Ku80 expression predicts locoregional failure and death following radiotherapy

Benjamin J. Moeller, John S. Yordy, Michelle D. Williams, Uma Giri, Uma Raju, David P. Molkentine, Lauren A. Byers, John V. Heymach, Michael D. Story, J. Jack Lee, Erich M. Sturgis, Randal S. Weber, Adam S. Garden, K. Kian Ang, David Schwartz

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Purpose: 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. Experimental Design: 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.

Original languageEnglish (US)
Pages (from-to)2035-2043
Number of pages9
JournalClinical Cancer Research
Volume17
Issue number7
DOIs
StatePublished - Apr 1 2011

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Head and Neck Neoplasms
DNA Repair
Radiotherapy
Biomarkers
Double-Stranded DNA Breaks
Proteins
Carcinoma, squamous cell of head and neck
Treatment Failure
Neoplasms
Research Design
Therapeutics
Radiation
Staining and Labeling
Survival
Mortality
Antibodies

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

DNA repair biomarker profiling of head and neck cancer : Ku80 expression predicts locoregional failure and death following radiotherapy. / Moeller, Benjamin J.; Yordy, John S.; Williams, Michelle D.; Giri, Uma; Raju, Uma; Molkentine, David P.; Byers, Lauren A.; Heymach, John V.; Story, Michael D.; Lee, J. Jack; Sturgis, Erich M.; Weber, Randal S.; Garden, Adam S.; Ang, K. Kian; Schwartz, David.

In: Clinical Cancer Research, Vol. 17, No. 7, 01.04.2011, p. 2035-2043.

Research output: Contribution to journalArticle

Moeller, BJ, Yordy, JS, Williams, MD, Giri, U, Raju, U, Molkentine, DP, Byers, LA, Heymach, JV, Story, MD, Lee, JJ, Sturgis, EM, Weber, RS, Garden, AS, Ang, KK & Schwartz, D 2011, 'DNA repair biomarker profiling of head and neck cancer: Ku80 expression predicts locoregional failure and death following radiotherapy', Clinical Cancer Research, vol. 17, no. 7, pp. 2035-2043. https://doi.org/10.1158/1078-0432.CCR-10-2641
Moeller, Benjamin J. ; Yordy, John S. ; Williams, Michelle D. ; Giri, Uma ; Raju, Uma ; Molkentine, David P. ; Byers, Lauren A. ; Heymach, John V. ; Story, Michael D. ; Lee, J. Jack ; Sturgis, Erich M. ; Weber, Randal S. ; Garden, Adam S. ; Ang, K. Kian ; Schwartz, David. / DNA repair biomarker profiling of head and neck cancer : Ku80 expression predicts locoregional failure and death following radiotherapy. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 7. pp. 2035-2043.
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T2 - Ku80 expression predicts locoregional failure and death following radiotherapy

AU - Moeller, Benjamin J.

AU - Yordy, John S.

AU - Williams, Michelle D.

AU - Giri, Uma

AU - Raju, Uma

AU - Molkentine, David P.

AU - Byers, Lauren A.

AU - Heymach, John V.

AU - Story, Michael D.

AU - Lee, J. Jack

AU - Sturgis, Erich M.

AU - Weber, Randal S.

AU - Garden, Adam S.

AU - Ang, K. Kian

AU - Schwartz, David

PY - 2011/4/1

Y1 - 2011/4/1

N2 - Purpose: 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. Experimental Design: 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.

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