Renal clear cell carcinomas have the highest proportion of indels, which are linked to immune activation.
Major finding: Renal clear cell carcinomas have the highest proportion of indels, which are linked to immune activation.
Concept: Frameshift indels are associated with a greater response to anti–PD-1 than nonsynonymous SNVs.
Impact: Frameshift indels may be potential biomarkers of response to immune checkpoint inhibitors.
Tumor-specific neoantigens are the targets of T cells in the context of checkpoint inhibitors or adoptive T-cell transfer. However, analyses of tumor-specific antigens have focused on single nucleotide variants (SNV), and the effects of small-scale insertions and deletions (indel) are less well understood. It has been hypothesized that frameshift indels may produce a large quantity of mutagenic neoantigenic peptides distinct from self, prompting Turajlic, Litchfield, and colleagues to investigate the effect of indels on the immunogenic phenotype. Analysis of whole-exome sequencing data from 5,777 solid tumors across 19 tumor types from The Cancer Genome Atlas (TCGA) revealed that renal clear cell carcinoma had the highest proportion of coding indels, 2.4 times higher than the pan-cancer average, and this observation was validated in two independent cohorts. Renal papillary cell carcinoma and chromophobe renal cell carcinoma also had elevated indel frequencies, suggesting a tissue-specific mutational process. Analysis of TCGA indels predicted 2 neoantigens per frameshift mutation in contrast to 0.64 neoantigens per nonsynonymous SNV and a 9-fold enrichment of mutant-specific neoantigens. Consistent with increased neoantigen generation, patients with melanoma harboring frameshift indel mutations exhibited a greater response to anti–PD-1 therapies than patients with nonsynonymous SNVs or in-frame indels. Similarly, RNA sequencing of tumors from patients with renal clear cell carcinoma revealed that a high load of frameshift neoantigens was associated with high expression of genes linked to immune activation, including genes involved in MHC class I antigen presentation and CD8+ T-cell activation. The finding that indels are a highly immunogenic mutation class that generate abundant neoantigens and may be associated with response to checkpoint inhibitors suggests that frameshift indels may serve as potential biomarkers of response to checkpoint blockade and as targets of tumor vaccines and cell therapies.
Turajlic S, Litchfield K, Xu H, Rosenthal R, McGranahan N, Reading JL, et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol 2017;18:1009–21.
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