Escape from nonsense mediated decay associates with anti-tumor immunogenicity
Frameshift insertion/deletions (fs-indels) are an infrequent but potentially highly immunogenic mutation subtype. Although fs-indel transcripts are susceptible to degradation through the non-sense mediated decay (NMD) pathway, we hypothesise that some fs-indels escape degradation and lead to an increased abundance of tumor specific neoantigens, that are highly distinct from self. We analysed matched DNA and RNA sequencing data from TCGA, and four separate melanoma cohorts treated with immunotherapy. Using allele-specific expression analysis we show that expressed fs-indels were enriched in genomic positions predicted to escape NMD, and associated with higher protein expression, consistent with degradation escape (“NMD-escape”). Given the strongly immunogenic potential, and relatively rare nature of NMD-escape fs-indels, these alterations may be attractive candidates in immunotherapy biomarker optimisation and neoantigen ACT or vaccine strategies.