Tissue microarray analysis of the essential DNA repair factors ATM, DNA-PKcs and KU80 in head and neck squamous cell carcinoma

Introduction: In HNSCC HPV-positivity confers favorable survival, in part through enhanced radiosensitivity, while HPV-negative tumors have remained a difficult to treat entity. So far, no predictive biomarker is established in any of the two groups. We therefore tested the impact of three potentially critical factors for intrinsic radiosensitivity, ATM, the central kinase of the DNA damage response, as well as DNA-PKcs and Ku80, two major factors in the main DNA repair pathway non-homologous end joining (NHEJ).

Materials and Methods: A tissue mircoarray (TMA) analysis of a single center HNSCC cohort was stained for ATM, DNA-PKcs, and Ku80. Staining intensity and the number of tumor cells stained were assessed, and expression was scored according to an established algorithm. Resulting scores were correlated with clinicopathological parameters and patient survival.

Results: Samples from 427 HNSCC patients yielded interpretable stainings. The majority of tumors showed strong expression of the NHEJ factors, whereas ATM expression was more variable. ATM and DNA-PKcs were not associated with patient survival. For Ku80 the minority of tumors not demonstrating strong expression trended towards superior survival in HPV-negative HNSCC patients, whose treatment included radiotherapy. Focusing stronger on staining intensity to define a relevant subgroup with the lowest expression levels, we observed significantly better overall survival for HPV-negative patients treated with radiotherapy but not if treated by surgery alone. Low Ku80 expression remained a significant factor in a multivariable analysis.

Conclusion: HPV-negative HNSCC with particularly low Ku80 expression may represent an especially radiosensitive subpopulation. Confirmation in independent cohorts is required.

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