Abstract
PurposePrior studies have demonstrated tumor-specific alternative splicing events in various solid tumor types. The role of alternative splicing in the development and progression of head and neck squamous cell carcinoma (HNSCC) is unclear. Our study queried exon-level expression to implicate splice variants in HNSCC tumors.Experimental DesignWe performed a comparative genome-wide analysis of 44 HNSCC tumors and 25 uvulopalatopharyngoplasty (UPPP) tissue samples at an exon expression level. In our comparison we ranked genes based upon a novel score—the Maximum-Minimum Exon Score (MMES) – designed to predict the likelihood of an alternative splicing event occurring. We validated predicted alternative splicing events using quantitative RT-PCR on an independent cohort.ResultsAfter MMES scoring of 17,422 genes, the top 900 genes with the highest scores underwent additional manual inspection of expression patterns in a graphical analysis. The genes LAMA3, DST, VEGFC, SDHA, RASIP1, and TP63 were selected for further validation studies because of a high frequency of alternative splicing suggested in our graphical analysis, and literature review showing their biological relevance and known splicing patterns. We confirmed TP63 as having dominant expression of the short DeltaNp63 isoform in HNSCC tumor samples, consistent with prior reports. Two of the six genes (LAMA3 and DST) validated by quantitative RT-PCR for tumor-specific alternative splicing events (Student's t test, P<0.001).ConclusionAlternative splicing events of oncologically relevant proteins occur in HNSCC. The number of genes expressing tumor-specific splice variants needs further elucidation, as does the functional significance of selective isoform expression.
Highlights
Head and neck squamous cell carcinoma (HNSCC) represents the sixth most prevalent solid tumor reported annually [1]
The genes LAMA3, DST, VEGFC, SDHA, RASIP1, and TP63 were selected for further validation studies because of a high frequency of alternative splicing suggested in our graphical analysis, and literature review showing their biological relevance and known splicing patterns
Alternative splicing events of oncologically relevant proteins occur in HNSCC
Summary
Head and neck squamous cell carcinoma (HNSCC) represents the sixth most prevalent solid tumor reported annually [1]. These tumors predominantly arise from the epithelia of the upper aerodigestive tract. The biological underpinnings explaining HNSCC tumorigenesis and diverse tumor behavior remain an area of ongoing investigation. Recent advances in understanding the genetic mutational landscape of HNSCC have shed light upon upregulated oncogenic and disrupted tumor suppressor pathways contributing to this disease. In addition to somatic mutations, additional drivers of tumorigenesis have been elucidated in HPV-associated oropharyngeal HNSCC, wherein human papilloma (HPV) viral oncogenic expression promotes degradation of important cell-cycle regulators such as retinoblastoma (Rb), thereby abrogating a critical tumor suppressor pathway [10]
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