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Hess J. ; Unger, K. ; Orth, M.* ; Schötz, U.* ; Schüttrumpf, L. ; Zangen, V. ; Gimenez-Aznar, I. ; Michna, A. ; Schneider, L. ; Stamp, R. ; Selmansberger, M. ; Braselmann, H. ; Hieber, L. ; Drexler, G.A.* ; Kuger, S. ; Klein, D.* ; Jendrossek, V.* ; Friedl, A.A. ; Belka, C. ; Zitzelsberger, H. ; Lauber, K.

Genomic amplification of Fanconi anemia complementation group A (FancA) in head and neck squamous cell carcinoma (HNSCC): Cellular mechanisms of radioresistance and clinical relevance.

Cancer Lett. 386, 87-99 (2017)
DOI
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Radio (chemo) therapy is a crucial treatment modality for head and neck squamous cell carcinoma (HNSCC), but relapse is frequent, and the underlying mechanisms remain largely elusive. Therefore, novel biomarkers are urgently needed. Previously, we identified gains on 16q23-24 to be associated with amplification of the Fanconi anemia A (FancA) gene and to correlate with reduced progression-free survival after radiotherapy. Here, we analyzed the effects of FancA on radiation sensitivity in vitro, characterized the underlying mechanisms, and evaluated their clinical relevance. Silencing of FancA expression in HNSCC cell lines with genomic gains on 16q23-24 resulted in significantly impaired clonogenic survival upon irradiation. Conversely, overexpression of FancA in immortalized keratinocytes conferred increased survival accompanied by improved DNA repair, reduced accumulation of chromosomal translocations, but no hyperactivation of the FA/BRCA-pathway. Downregulation of interferon signaling as identified by microarray analyses, enforced irradiation-induced senescence, and elevated production of the senescence-associated secretory phenotype (SASP) appeared to be candidate mechanisms contributing to FancA-mediated radioresistance. Data of the TCGA HNSCC cohort confirmed the association of gains on 16q24.3 with FancA overexpression and impaired overall survival. Importantly, transcriptomic alterations similar to those observed upon FancA overexpression in vitro strengthened the clinical relevance. Overall, FancA amplification and overexpression appear to be crucial for radiotherapeutic failure in HNSCC.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Dna Damage Repair ; Fanconi Anemia ; Head And Neck Squamous Cell Carcinoma ; Radioresistance ; Radiotherapy ; Senescence; Nf-kappa-b; Dna-damage Response; Radiation Sensitivity; Human-papillomavirus; Interaction Networks; Secretory Phenotype; Tumor Suppression; Down-regulation; Cancer-cells; Core Complex
ISSN (print) / ISBN 0304-3835
e-ISSN 0304-3835
Zeitschrift Cancer Letters
Quellenangaben Band: 386, Heft: , Seiten: 87-99 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort Clare
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Radiation Cytogenetics (ZYTO)
CCG Personalized Radiotherapy in Head and Neck Cancer (KKG-KRT)