دورية أكاديمية
Dr.Nod: computational framework for discovery of regulatory non-coding drivers in tissue-matched distal regulatory elements
| العنوان: | Dr.Nod: computational framework for discovery of regulatory non-coding drivers in tissue-matched distal regulatory elements |
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| المؤلفون: | Tomkova, M, Tomek, J, Chow, J, McPherson, JD, Segal, DJ, Hormozdiari, F |
| بيانات النشر: | Oxford University Press |
| سنة النشر: | 2023 |
| المجموعة: | Oxford University Research Archive (ORA) |
| مصطلحات موضوعية: | Polymorphism/mutation detection |
| الوصف: | The discovery of cancer driver mutations is a fundamental goal in cancer research. While many cancer driver mutations have been discovered in the protein-coding genome, research into potential cancer drivers in the non-coding regions showed limited success so far. Here, we present a novel comprehensive framework Dr.Nod for detection of non-coding cis-regulatory candidate driver mutations that are associated with dysregulated gene expression using tissue-matched enhancer-gene annotations. Applying the framework to data from over 1500 tumours across eight tissues revealed a 4.4-fold enrichment of candidate driver mutations in regulatory regions of known cancer driver genes. An overarching conclusion that emerges is that the non-coding driver mutations contribute to cancer by significantly altering transcription factor binding sites, leading to upregulation of tissue-matched oncogenes and down-regulation of tumour-suppressor genes. Interestingly, more than half of the detected cancer-promoting non-coding regulatory driver mutations are over 20 kb distant from the cancer-associated genes they regulate. Our results show the importance of tissue-matched enhancer-gene maps, functional impact of mutations, and complex background mutagenesis model for the prediction of non-coding regulatory drivers. In conclusion, our study demonstrates that non-coding mutations in enhancers play a previously underappreciated role in cancer and dysregulation of clinically relevant target genes. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | https://ora.ox.ac.uk/objects/uuid:3be03896-a749-4cbf-b245-807738245fbcTest; https://doi.org/10.1093/nar/gkac1251Test |
| DOI: | 10.1093/nar/gkac1251 |
| الإتاحة: | https://doi.org/10.1093/nar/gkac1251Test https://ora.ox.ac.uk/objects/uuid:3be03896-a749-4cbf-b245-807738245fbcTest |
| حقوق: | info:eu-repo/semantics/openAccess ; CC Attribution (CC BY) |
| رقم الانضمام: | edsbas.B469F3CB |
| قاعدة البيانات: | BASE |
| DOI: | 10.1093/nar/gkac1251 |
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