title: Nuclear p16INK4a expression predicts enhanced radiation response in head and neck cancers.
abstract: Immunohistochemistry analysis of p16INK4a in head and neck squamous cell carcinomas (HNSCC) tumor samples revealed that 28% of tumors showed nuclear/cytoplasmic p16INK4a localization, while 37% of tumors had cytoplasmic p16INK4a. Our previous study showed that p16INK4a inhibits the DNA repair response independently of its function in the cell cycle, suggesting that p16INK4a subcellular localization should be considered during stratification of HNSCC patients.Using p16INK4a mutants with different localization signals, we found that expression of nuclear p16INK4a, but not cytoplasmic p16INK4a impaired RAD51 foci formation, indicating that nuclear localization of p16INK4a is crucial for its function in DNA repair. We next investigated the role of p16INK4a subcellular localization in radiation response in a retrospective cohort of 261 HNSCC patients treated with chemoradiation. We found that only HNSCC patients expressing nuclear p16INK4a expression showed better outcome, locoregional control and disease free survival, after chemoradiation. In concordance with the patient data, only expression of nuclear p16INK4a increased radiosensitivity of HNSCC cells. These results implicate nuclear p16INK4a expression as a potent marker to predict radiation response of HNSCC patients and should be taken into account in intensification or de-escalation studies.
authors.affiliation: Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, University of Leuven, Leuven, Belgium.
authors.forename: Rüveyda
authors.initials: R
authors.lastname: Dok
authors.affiliation: VIB Center for the Biology of Disease, Leuven, Belgium.|Department of Human Genetics, KU Leuven, University of Leuven, Leuven, Belgium.
authors.forename: Layka
authors.initials: L
authors.lastname: Abbasi Asbagh
authors.affiliation: Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, University of Leuven, Leuven, Belgium.|Department of Radiation Oncology, Leuven Cancer Institute, UZ Leuven, Leuven, Belgium.|Current address: Maastro Clinic, Maastricht, The Netherlands.
authors.forename: Evert Jan
authors.initials: EJ
authors.lastname: Van Limbergen
authors.affiliation: VIB Center for the Biology of Disease, Leuven, Belgium.|Department of Human Genetics, KU Leuven, University of Leuven, Leuven, Belgium.
authors.forename: Anna
authors.initials: A
authors.lastname: Sablina
authors.affiliation: Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, University of Leuven, Leuven, Belgium.|Department of Radiation Oncology, Leuven Cancer Institute, UZ Leuven, Leuven, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: Nuyts
mesh_terms: D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009959:Oropharyngeal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D027383:Papillomaviridae; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18
keywords: DNA repair; HPV; head and neck cancers; nuclear p16INK4a expression; radiotherapy