Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK; Renal and Skin Units, The Royal Marsden Hospital National Health Service Foundation Trust, London, UK.
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
Lancet Oncol. 2017 Aug;18(8):1009-1021. doi: 10.1016/S1470-2045(17)30516-8. Epub 2017 Jul 7.
The focus of tumour-specific antigen analyses has been on single nucleotide variants (SNVs), with the contribution of small insertions and deletions (indels) less well characterised. We investigated whether the frameshift nature of indel mutations, which create novel open reading frames and a large quantity of mutagenic peptides highly distinct from self, might contribute to the immunogenic phenotype.
We analysed whole-exome sequencing data from 5777 solid tumours, spanning 19 cancer types from The Cancer Genome Atlas. We compared the proportion and number of indels across the cohort, with a subset of results replicated in two independent datasets. We assessed in-silico tumour-specific neoantigen predictions by mutation type with pan-cancer analysis, together with RNAseq profiling in renal clear cell carcinoma cases (n=392), to compare immune gene expression across patient subgroups. Associations between indel burden and treatment response were assessed across four checkpoint inhibitor datasets.
We observed renal cell carcinomas to have the highest proportion (0·12) and number of indel mutations across the pan-cancer cohort (p<2·2 × 10), more than double the median proportion of indel mutations in all other cancer types examined. Analysis of tumour-specific neoantigens showed that enrichment of indel mutations for high-affinity binders was three times that of non-synonymous SNV mutations. Furthermore, neoantigens derived from indel mutations were nine times enriched for mutant specific binding, as compared with non-synonymous SNV derived neoantigens. Immune gene expression analysis in the renal clear cell carcinoma cohort showed that the presence of mutant-specific neoantigens was associated with upregulation of antigen presentation genes, which correlated (r=0·78) with T-cell activation as measured by CD8-positive expression. Finally, analysis of checkpoint inhibitor response data revealed frameshift indel count to be significantly associated with checkpoint inhibitor response across three separate melanoma cohorts (p=4·7 × 10).
Renal cell carcinomas have the highest pan-cancer proportion and number of indel mutations. Evidence suggests indels are a highly immunogenic mutational class, which can trigger an increased abundance of neoantigens and greater mutant-binding specificity.
Cancer Research UK, UK National Institute for Health Research (NIHR) at the Royal Marsden Hospital National Health Service Foundation Trust, Institute of Cancer Research and University College London Hospitals Biomedical Research Centres, the UK Medical Research Council, the Rosetrees Trust, Novo Nordisk Foundation, the Prostate Cancer Foundation, the Breast Cancer Research Foundation, the European Research Council.
肿瘤特异性抗原分析的重点一直是单核苷酸变异（SNVs），而较小的插入和缺失（indels）的贡献则不太清楚。我们研究了插入缺失突变的移码性质是否会导致新的开放阅读框和大量与自身高度不同的诱变肽，从而有助于免疫表型。
我们分析了来自 5777 个实体瘤的全外显子组测序数据，涵盖了癌症基因组图谱中的 19 种癌症类型。我们比较了整个队列中插入缺失的比例和数量，部分结果在两个独立的数据集进行了重复验证。我们通过泛癌症分析，评估了突变类型的肿瘤特异性新抗原预测，并在肾透明细胞癌病例（n=392）中进行了 RNAseq 分析，以比较患者亚组之间的免疫基因表达。我们在四个检查点抑制剂数据集中评估了插入缺失负担与治疗反应之间的关联。
我们观察到肾细胞癌在泛癌症队列中具有最高比例（0.12）和数量的插入缺失突变（p<2.2 × 10），是所有其他检查的癌症类型中插入缺失突变中位数的两倍多。肿瘤特异性新抗原分析表明，高亲和力结合物的插入缺失突变富集程度是非同义 SNV 突变的三倍。此外，与非同义 SNV 衍生的新抗原相比，插入缺失突变衍生的新抗原在突变特异性结合方面富集了九倍。肾透明细胞癌队列中的免疫基因表达分析表明，存在突变特异性新抗原与抗原呈递基因的上调相关，这与通过 CD8 阳性表达测量的 T 细胞激活相关（r=0.78）。最后，检查点抑制剂反应数据分析显示，框架移位插入缺失计数与三个独立的黑色素瘤队列中的检查点抑制剂反应显著相关（p=4.7 × 10）。
肾细胞癌在泛癌症中具有最高的比例和数量的插入缺失突变。有证据表明插入缺失是一种高度免疫原性的突变类型，可引发新抗原的丰度增加，并增加突变结合的特异性。
英国癌症研究中心、英国国家卫生研究院（NIHR）在皇家马斯登医院国民保健信托基金会、癌症研究所和伦敦大学学院医院生物医学研究中心、英国医学研究理事会、罗斯特里基金会、诺和诺德基金会、前列腺癌基金会、乳腺癌研究基金会、欧洲研究理事会。
