Abstract
Head and neck squamous cell carcinoma (HNSCC) is characterized by the frequent manifestation of DNA crosslink repair defects. We established novel expression-based DNA repair defect markers to determine the clinical impact of such repair defects. Using hypersensitivity to theDNAcrosslinking agents, mitomycin C and olaparib, as proxies for functional DNA repair defects in a panel of 25 HNSCC cell lines, we applied machine learning to define gene expression models that predict repair defects. The expression profiles established predicted hypersensitivity to DNA-damaging agents and were associated with mutations in crosslink repair genes, as well as downregulation of DNA damage response and repair genes, in two independent datasets. The prognostic value of the repair defect prediction profiles was assessed in two retrospective cohorts with a total of 180 patients with advanced HPV-negative HNSCC, who were treated with cisplatin-based chemoradiotherapy. DNA repair defects, as predicted by the profiles, were associated with poor outcome in both patient cohorts. The poor prognosis association was particularly strong in normoxic tumor samples and was linked to an increased risk of distant metastasis. In vitro, only crosslink repair-defective HNSCC cell lines are highly migratory and invasive. This phenotype could also be induced in cells by inhibiting rad51 in repair competent and reduced by DNA-PK inhibition. In conclusion, DNA crosslink repair prediction expression profiles reveal a poor prognosis association in HNSCC.
| Original language | English |
|---|---|
| Pages (from-to) | 5597-5611 |
| Number of pages | 15 |
| Journal | Cancer Research |
| Volume | 79 |
| Issue number | 21 |
| DOIs | |
| Publication status | Published - 1 Nov 2019 |
Bibliographical note
Funding Information:This research was funded by the EU 7th framework program (257144 ARTFORCE), the Dutch Cancer Society (KWF-A6C7072, DESIGN consortium, to R.H. Brakenhoff, C. Vens, and M. van den Brekel) and the Brunel and Verwelius funds (to C. Vens and M. van den Brekel). We would like to thank the NKI Genomics Core Facility for performing RNA sequencing, the NKI RHPC facility for providing computational resources, and the Core Facility-Molecular Pathology and Biobank (CFMPB) for collecting and preparing tissue samples. We are thankful for B. Floot's help and the kind gift of UT-SCC lines from Professor Reidar Gr?nman (Turku University Hospital, Turku, Finland). We thank Robert W. Sobol (University South Alabama, Mobile, AL) for reviewing and providing editorial comments.
Funding Information:
This research was funded by the EU 7th framework program (257144 ARTFORCE), the Dutch Cancer Society (KWF-A6C7072, DESIGN consortium, to R.H. Brakenhoff, C. Vens, and M. van den Brekel) and the Brunel and Verwelius funds (to C. Vens and M. van den Brekel). We would like to thank the NKI Genomics Core Facility for performing RNA sequencing, the NKI RHPC facility for providing computational resources, and the Core Facility-Molecular Pathology and Biobank (CFMPB) for collecting and preparing tissue samples. We are thankful for B. Floot's help and the kind gift of UT-SCC lines from Professor Reidar Grénman (Turku University Hospital, Turku, Finland). We thank Robert W. Sobol (University South Alabama, Mobile, AL) for reviewing and providing editorial comments.
Publisher Copyright:
© 2019 American Association for Cancer Research.
