The immunogenic potential of recurrent cancer drug resistance mutations: an<i>in silico</i>study

Punta, Marco; Jennings, Victoria A.; Melcher, Alan; Lise, Stefano

doi:10.1101/845784

Cited by 2 publications

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References 66 publications

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“…This manuscript has been released as a Pre-Print at BioRxiv ( 78 ). This publication and the underlying study have been made possible partly on the basis of the data that the Hartwig Medical Foundation has made available to the study (Data Access Request: DR-134).…”

Section: Acknowledgmentsmentioning

confidence: 99%

The Immunogenic Potential of Recurrent Cancer Drug Resistance Mutations: An In Silico Study

et al. 2020

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Cancer somatic mutations have been identified as a source of antigens that can be targeted by cancer immunotherapy. In this work, expanding on previous studies, we analyze the HLA-presentation properties of mutations that are known to drive resistance to cancer targeted-therapies. We survey a large dataset of mutations that confer resistance to different drugs and occur in numerous genes and tumor types. We show that a significant number of them are predicted in silico to be potentially immunogenic across a large proportion of the human population. Further, by analyzing a cohort of patients carrying a small subset of these resistance mutations, we provide evidence that what is observed in the general population may be indicative of the mutations’ immunogenic potential in resistant patients. Two of the mutations in our dataset had previously been experimentally validated by others and it was confirmed that some of their associated neopeptides elicit T-cell responses in vitro . The identification of potent cancer-specific antigens can be instrumental for developing more effective immunotherapies. In this work, we propose a novel list of drug-resistance mutations, several of which are recurrent, that could be of particular interest in the context of off-the-shelf precision immunotherapies such as therapeutic cancer vaccines.

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Section: Acknowledgmentsmentioning

confidence: 99%

The Immunogenic Potential of Recurrent Cancer Drug Resistance Mutations: An In Silico Study

et al. 2020

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Clinical BRCA1/2 Reversion Analysis Identifies Hotspot Mutations and Predicted Neoantigens Associated with Therapy Resistance

et al. 2020

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Reversion mutations in BRCA1 or BRCA2 are associated with resistance to PARP inhibitors and platinum. To better understand the nature of these mutations, we collated, codifi ed, and analyzed more than 300 reversions. This identifi ed reversion "hotspots" and "deserts" in regions encoding the N and C terminus, respectively, of BRCA2, suggesting that pathogenic mutations in these regions may be at higher or lower risk of reversion. Missense and splice-site pathogenic mutations in BRCA1/2 also appeared less likely to revert than truncating mutations. Most reversions were <100 bp deletions. Although many deletions exhibited microhomology, this was not universal, suggesting that multiple DNA-repair processes cause reversion. Finally, we found that many reversions were predicted to encode immunogenic neopeptides, suggesting a route to the treatment of reverted disease. As well as providing a freely available database for the collation of future reversion cases, these observations have implications for how drug resistance might be managed in BRCA -mutant cancers. SIGNIFICANCE: Reversion mutations in BRCA genes are a major cause of clinical platinum and PARP inhibitor resistance. This analysis of all reported clinical reversions suggests that the position of BRCA2 mutations affects the risk of reversion. Many reversions are also predicted to encode tumor neoantigens, providing a potential route to targeting resistance.

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The immunogenic potential of recurrent cancer drug resistance mutations: anin silicostudy

Cited by 2 publications

References 66 publications

The Immunogenic Potential of Recurrent Cancer Drug Resistance Mutations: An In Silico Study

The Immunogenic Potential of Recurrent Cancer Drug Resistance Mutations: An In Silico Study

Clinical BRCA1/2 Reversion Analysis Identifies Hotspot Mutations and Predicted Neoantigens Associated with Therapy Resistance

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