Genomic amplification of Fanconi anemia complementation group A (FancA) in head and neck squamous cell carcinoma (HNSCC): Cellular mechanisms of radioresistance and clinical relevance. (1st February 2017)

• Record Type: Journal Article
• Authors: Hess, Julia; Unger, Kristian; Orth, Michael; Schötz, Ulrike; Schüttrumpf, Lars; Zangen, Verena; Gimenez-Aznar, Igor; Michna, Agata; Schneider, Ludmila; Stamp, Ramona; Selmansberger, Martin; Braselmann, Herbert; Hieber, Ludwig; Drexler, Guido A.; Kuger, Sebastian; Klein, Diana; Jendrossek, Verena; Friedl, Anna A.; Belka, Claus; Zitzelsberger, Horst; Lauber, Kirsten
• Is Part Of: Cancer letters. Volume 386(2017)
• Page Start: 87
• Page End: 99
• Publication Date: 2017-02-01
• Subjects: Head and neck squamous cell carcinoma -- Fanconi anemia -- Radiotherapy -- Radioresistance -- Senescence -- DNA damage repair; Array CGH Microarray-based comparative genomic hybridization -- ATM Ataxia telangiectasia mutated -- C12-FDG-FITC 5-dodecanoylaminofluorescein-di-β-galactopyranoside -- cGAS cyclic GMP-AMP synthase -- FancA Fanconi anemia complementation group A -- FDR false discovery rate -- FFPE formalin-fixed paraffin-embedded -- FISH fluorescence in situ hybridization -- HNSCC head and neck squamous cell carcinoma -- IFN interferon -- LRP locoregional progression -- PI propidium iodide -- qRT-PCR quantitative realtime reverse transcription polymerase chain reaction -- SA-β-gal senescence-associated β-galactosidase -- SKY spectral karyotyping -- TERT1 telomerase reverse transcriptase 1; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2016.11.014
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: Gains on 16q24.3 associate with FancA overexpression and impaired overall survival. FancA overexpression confers radioresistance with improved DNA repair in vitro . No hyperactivation of the FA/BRCA-pathway is observed. Interferon signaling is attenuated, senescence, and SASP production are enforced. FancA-associated transcriptomic alterations are reflected in clinical HNSCC samples.