Abstract
BackgroundRadiotherapy for head and neck squamous cell carcinomas (HNSCC) is associated with a substantial morbidity and inconsistent efficacy. Human papillomavirus (HPV)-positive status is recognized as a marker of increased radiosensitivity. Our goal was to identify molecular markers associated with benefit to radiotherapy in patients with HPV-negative disease.MethodsGene expression profiles from public repositories were downloaded for data mining. Training sets included 421 HPV-negative HNSCC tumors from The Cancer Genome Atlas (TCGA) and 32 HNSCC cell lines with available radiosensitivity data (GSE79368). A radioresistance (RadR) score was computed using the single sample Gene Set Enrichment Analysis tool. The validation sets included two panels of cell lines (NCI-60 and GSE21644) and HPV-negative HNSCC tumor datasets, including 44 (GSE6631), 82 (GSE39366), and 179 (GSE65858) patients, respectively. We finally performed an integrated analysis of the RadR score with known recurrent genomic alterations in HNSCC, patterns of protein expression, biological hallmarks, and patterns of drug sensitivity using TCGA and the E-MTAB-3610 dataset (659 pancancer cell lines, 140 drugs).ResultsWe identified 13 genes differentially expressed between tumor and normal head and neck mucosa that were associated with radioresistance in vitro and in patients. The 13-gene expression-based RadR score was associated with recurrence in patients treated with surgery and adjuvant radiotherapy but not with surgery alone. It was significantly different among different molecular subtypes of HPV-negative HNSCC and was significantly lower in the “atypical” molecular subtype. An integrated analysis of RadR score with genomic alterations, protein expression, biological hallmarks and patterns of drug sensitivity showed a significant association with CCND1 amplification, fibronectin expression, seven hallmarks (including epithelial-to-mesenchymal transition and unfolded protein response), and increased sensitivity to elesclomol, an HSP90 inhibitor.ConclusionsOur study highlights the clinical relevance of the molecular classification of HNSCC and the RadR score to refine radiation strategies in HPV-negative disease.
Highlights
Radiotherapy for head and neck squamous cell carcinomas (HNSCC) is associated with a substantial morbidity and inconsistent efficacy
We found the RadR score to be (1) associated with poor disease freesurvival (DFS) in human papillomavirus (HPV)-negative HNSCC patients treated by surgery and radiotherapy but not in patients treated with surgery alone; (2) lower in the HPV-negative atypical molecular subtype and higher in the mesenchymal subtype; and (3) significantly associated with CCND1 amplification, fibronectin expression and seven biological hallmarks, including the ENT and the actionable “unfolded protein response” hallmarks
Identification of radioresistance-associated genes in HPV-negative HNSCC A sequential approach was used to select genes associated with radioresistance, by selecting (1) genes differentially expressed in tumor versus normal head and neck samples; (2) genes associated with in vitro radioresistance, and (3) genes associated with a poor DFS in patients treated by surgery and radiotherapy (Fig. 1)
Summary
Radiotherapy for head and neck squamous cell carcinomas (HNSCC) is associated with a substantial morbidity and inconsistent efficacy. Several approaches have been used to predict the tumor response to radiotherapy, including functional assays (clonogenic cell survival [5] or DNA repair [6]) or omics-based biomarkers [3, 7,8,9,10]. The latter have been identified in cancer cell lines and their expression in normal cells has not been evaluated. The potential impact of normal tissue contaminating the tumor sample on intrinsic radioresistance has to be considered
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