Samra Turajlic1, Kevin Litchfield2, Hang Xu2, Rachel Rosenthal3, Nicholas McGranahan4, James L Reading5, Yien Ning S Wong5, Andrew Rowan2, Nnennaya Kanu3, Maise Al Bakir2, Tim Chambers2, Roberto Salgado6, Peter Savas7, Sherene Loi7, Nicolai J Birkbak2, Laurent Sansregret2, Martin Gore8, James Larkin8, Sergio A Quezada5, Charles Swanton9. 1. 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. 2. Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK. 3. Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, London, UK. 4. Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, London, UK. 5. Cancer Immunology Unit, Research Department of Haematology, London, UK. 6. Department of Pathology, Gasthuiszusters, Antwerp, Belgium; Division of Research and Cancer Medicine, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia. 7. Division of Research and Cancer Medicine, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia. 8. Renal and Skin Units, The Royal Marsden Hospital National Health Service Foundation Trust, London, UK. 9. Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, London, UK; Department of Medical Oncology, University College London Hospitals, London, UK. Electronic address: charles.swanton@crick.ac.uk.
Abstract
BACKGROUND: 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. METHODS: 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. FINDINGS: 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 × 10-16), 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 × 10-4). INTERPRETATION: 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. FUNDING: 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.
BACKGROUND: 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. METHODS: 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. FINDINGS: 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 × 10-16), 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 × 10-4). INTERPRETATION: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. FUNDING: 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.
Authors: Siwen Hu-Lieskovan; Srabani Bhaumik; Kavita Dhodapkar; Jean-Charles J B Grivel; Sumati Gupta; Brent A Hanks; Sylvia Janetzki; Thomas O Kleen; Yoshinobu Koguchi; Amanda W Lund; Cristina Maccalli; Yolanda D Mahnke; Ruslan D Novosiadly; Senthamil R Selvan; Tasha Sims; Yingdong Zhao; Holden T Maecker Journal: J Immunother Cancer Date: 2020-12 Impact factor: 13.751
Authors: Rong Lu; Payal Kapur; Bijay S Jaiswal; Tao Wang; Raquibul Hannan; Ze Zhang; Ivan Pedrosa; Jason J Luke; He Zhang; Leonard D Goldstein; Qurratulain Yousuf; Yi-Feng Gu; Tiffani McKenzie; Allison Joyce; Min S Kim; Xinlei Wang; Danni Luo; Oreoluwa Onabolu; Christina Stevens; Zhiqun Xie; Mingyi Chen; Alexander Filatenkov; Jose Torrealba; Xin Luo; Wenbin Guo; Jingxuan He; Eric Stawiski; Zora Modrusan; Steffen Durinck; Somasekar Seshagiri; James Brugarolas Journal: Cancer Discov Date: 2018-06-08 Impact factor: 39.397