title: Genomic amplification of Fanconi anemia complementation group A (FancA) in head and neck squamous cell carcinoma (HNSCC): Cellular mechanisms of radioresistance and clinical relevance.
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.
authors.affiliation: Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany; Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany. Electronic address: julia.hess@helmholtz-muenchen.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Hess
authors.affiliation: Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany; Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany. Electronic address: unger@helmholtz-muenchen.de.
authors.forename: Kristian
authors.initials: K
authors.lastname: Unger
authors.affiliation: Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University, 81377 Munich, Germany. Electronic address: michael.orth@med.uni-muenchen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Orth
authors.affiliation: Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University, 81377 Munich, Germany. Electronic address: ulrike.schoetz@med.uni-muenchen.de.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schötz
authors.affiliation: Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University, 81377 Munich, Germany; Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany. Electronic address: lars.schuettrumpf@med.uni-muenchen.de.
authors.forename: Lars
authors.initials: L
authors.lastname: Schüttrumpf
authors.affiliation: Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany; Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany. Electronic address: verena.zangen@helmholtz-muenchen.de.
authors.forename: Verena
authors.initials: V
authors.lastname: Zangen
authors.affiliation: Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany. Electronic address: igor.gimenez-aznar@helmholtz-muenchen.de.
authors.forename: Igor
authors.initials: I
authors.lastname: Gimenez-Aznar
authors.affiliation: Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany. Electronic address: agata.michna@helmholtz-muenchen.de.
authors.forename: Agata
authors.initials: A
authors.lastname: Michna
authors.affiliation: Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany; Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany. Electronic address: ludmila.schneider@helmholtz-muenchen.de.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Schneider
authors.affiliation: Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University, 81377 Munich, Germany; Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany. Electronic address: ramona.stamp@googlemail.com.
authors.forename: Ramona
authors.initials: R
authors.lastname: Stamp
authors.affiliation: Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany. Electronic address: martin.selmansberger@helmholtz-muenchen.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Selmansberger
authors.affiliation: Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany; Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany. Electronic address: braselm@helmholtz-muenchen.de.
authors.forename: Herbert
authors.initials: H
authors.lastname: Braselmann
authors.affiliation: Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany; Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany. Electronic address: ludwig.hieber@arcor.de.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Hieber
authors.affiliation: Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University, 81377 Munich, Germany. Electronic address: guido.drexler@lrz.uni-muenchen.de.
authors.forename: Guido A
authors.initials: GA
authors.lastname: Drexler
authors.affiliation: Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany; Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany. Electronic address: sebastian.kuger@helmholtz-muenchen.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kuger
authors.affiliation: Institute for Cell Biology (Cancer Research), University of Duisburg-Essen, 45122 Essen, Germany. Electronic address: Diana.Klein@uk-essen.de.
authors.forename: Diana
authors.initials: D
authors.lastname: Klein
authors.affiliation: Institute for Cell Biology (Cancer Research), University of Duisburg-Essen, 45122 Essen, Germany. Electronic address: verena.jendrossek@uni-due.de.
authors.forename: Verena
authors.initials: V
authors.lastname: Jendrossek
authors.affiliation: Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University, 81377 Munich, Germany; Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany. Electronic address: anna.Friedl@med.uni-muenchen.de.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Friedl
authors.affiliation: Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University, 81377 Munich, Germany; Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany. Electronic address: claus.belka@med.uni-muenchen.de.
authors.forename: Claus
authors.initials: C
authors.lastname: Belka
authors.affiliation: Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany; Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany. Electronic address: zitzelsberger@helmholtz-muenchen.de.
authors.forename: Horst
authors.initials: H
authors.lastname: Zitzelsberger
authors.affiliation: Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University, 81377 Munich, Germany; Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany. Electronic address: kirsten.lauber@med.uni-muenchen.de.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Lauber
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics*; D005784:Gene Amplification; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D053208:Kaplan-Meier Estimate; D015603:Keratinocytes / Q000473:pathology / Q000528:radiation effects; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics*; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors; D014162:Transfection; D017211:Treatment Failure; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C498471:FANCA protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: DNA damage repair; Fanconi anemia; Head and neck squamous cell carcinoma; Radioresistance; Radiotherapy; Senescence