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. 2017 Feb 1:386:87-99. doi: 10.1016/j.canlet.2016.11.014. Epub 2016 Nov 17.


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.

Keywords: DNA damage repair; Fanconi anemia; Head and neck squamous cell carcinoma; Radioresistance; Radiotherapy; Senescence.

MeSH terms

  • Biomarkers, Tumor / genetics*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / mortality
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / radiotherapy*
  • Cell Line, Tumor
  • Cellular Senescence / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Disease-Free Survival
  • Fanconi Anemia Complementation Group A Protein / genetics*
  • Gene Amplification*
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Genotype
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / mortality
  • Head and Neck Neoplasms / pathology
  • Head and Neck Neoplasms / radiotherapy*
  • Humans
  • Kaplan-Meier Estimate
  • Keratinocytes / pathology
  • Keratinocytes / radiation effects
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Radiation Tolerance / genetics*
  • Squamous Cell Carcinoma of Head and Neck
  • Time Factors
  • Transfection
  • Treatment Failure
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism


  • Biomarkers, Tumor
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • FANCA protein, human
  • Fanconi Anemia Complementation Group A Protein
  • RNA, Messenger
  • TP53 protein, human
  • Tumor Suppressor Protein p53