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Published on: June 9, 2017
Tissue microarray analyses of the essential DNA repair factors ATM, DNA-PKcs and Ku80 in head and neck squamous cell
Henrike Barbara Zech1, Clara von Bargen2, Agnes Oetting1,3
1Department of Otorhinolaryngology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Background:
Head and neck squamous cell carcinoma (HNSCC) negative for Human Papillomavirus (HPV) has remained a difficult to treat entity, whereas tumors positive for HPV are characterized by radiosensitivity and favorable patient outcome. On the cellular level, radiosensitivity is largely governed by the tumor cells` ability to repair radiation-induced DNA double-strand breaks (DSBs), but no biomarker is established that could guide clinical decision making. Therefore, we tested the impact of the expression levels of ATM, the central kinase of the DNA damage response as well as DNA-PKcs and Ku80, two major factors in the main DSB repair pathway non-homologous end joining (NHEJ).
Methods:
A tissue microarray of a single center HNSCC cohort was stained for ATM, DNA-PKcs and Ku80 and the expression scored based on staining intensity and the percentages of tumor cells stained. Scores were correlated with clinicopathological parameters and survival.
Results:
Samples from 427 HNSCC patients yielded interpretable stainings and were scored following an established algorithm. The majority of tumors showed strong expression of both NHEJ factors, whereas the expression of ATM varied more. The expression scores of ATM and DNA-PKcs were not associated with patient survival. For HPV-negative HNSCC, the minority of tumors without strong Ku80 expression trended towards superior survival when treatment included radiotherapy. Focusing stronger on staining intensity to define the subgroup with lowest and therefore potentially insufficient expression levels in the HPV-negative subgroup, we observed significantly better overall survival for patients treated with radiotherapy but not with surgery alone.
Conclusions:
Our data suggest that HPV-negative HNSCC with particularly low Ku80 expression represent a highly radiosensitive subpopulation. Confirmation in independent cohorts is required.
Insights
Low Ku80 expression in Human Papillomavirus-negative head and neck squamous cell carcinoma indicates higher radiosensitivity. This finding may identify a subpopulation of HPV-negative HNSCC patients who benefit from radiotherapy.
Area of Science:
- Oncology
- Radiation Oncology
- Molecular Biology
Background:
- Head and neck squamous cell carcinoma (HNSCC) that is negative for Human Papillomavirus (HPV) is challenging to treat.
- HPV-positive HNSCC generally shows radiosensitivity and better patient outcomes.
- Radiosensitivity is linked to the tumor's ability to repair DNA double-strand breaks (DSBs), but a reliable biomarker is lacking.
Purpose of the Study:
- To investigate the expression of ATM, DNA-PKcs, and Ku80 in HNSCC.
- To determine if these proteins are biomarkers for radiosensitivity and patient survival in HPV-negative HNSCC.
Main Methods:
- A tissue microarray from 427 HNSCC patients was stained for ATM, DNA-PKcs, and Ku80.
- Protein expression was scored based on staining intensity and percentage of positive tumor cells.
- Scores were correlated with clinicopathological parameters and patient survival.
Main Results:
- ATM and DNA-PKcs expression did not correlate with patient survival.
- In HPV-negative HNSCC, tumors with low Ku80 expression showed a trend towards better survival with radiotherapy.
- Specifically, HPV-negative HNSCC with the lowest Ku80 expression levels demonstrated significantly better overall survival when treated with radiotherapy compared to surgery alone.
Conclusions:
- Low Ku80 expression identifies a potential subpopulation of HPV-negative HNSCC patients who are highly radiosensitive.
- Further validation in independent cohorts is necessary to confirm these findings.
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