Gimeno-Valiente, F., Castignani, C., Larose Cadieux, E. orcid.org/0000-0002-9320-8040 et al. (265 more authors) (2025) DNA methylation cooperates with genomic alterations during non-small cell lung cancer evolution. Nature Genetics, 57 (9). pp. 2226-2237. ISSN: 1061-4036
Abstract
Aberrant DNA methylation has been described in nearly all human cancers, yet its interplay with genomic alterations during tumor evolution is poorly understood. To explore this, we performed reduced representation bisulfite sequencing on 217 tumor and matched normal regions from 59 patients with non-small cell lung cancer from the TRACERx study to deconvolve tumor methylation. We developed two metrics for integrative evolutionary analysis with DNA and RNA sequencing data. Intratumoral methylation distance quantifies intratumor DNA methylation heterogeneity. MR/MN classifies genes based on the rate of hypermethylation at regulatory (MR) versus nonregulatory (MN) CpGs to identify driver genes exhibiting recurrent functional hypermethylation. We identified DNA methylation-linked dosage compensation of essential genes co-amplified with neighboring oncogenes. We propose two complementary mechanisms that converge for copy number alteration-affected chromatin to undergo the epigenetic equivalent of an allosteric activity transition. Hypermethylated driver genes under positive selection may open avenues for therapeutic stratification of patients.
Metadata
| Item Type: | Article |
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| Copyright, Publisher and Additional Information: | © The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Humans; DNA Methylation; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; CpG Islands; DNA Copy Number Variations; Gene Expression Regulation, Neoplastic; Epigenesis, Genetic; Evolution, Molecular |
| Dates: |
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| Institution: | The University of Sheffield |
| Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health |
| Date Deposited: | 30 Oct 2025 15:20 |
| Last Modified: | 30 Oct 2025 15:20 |
| Status: | Published |
| Publisher: | Springer Science and Business Media LLC |
| Refereed: | Yes |
| Identification Number: | 10.1038/s41588-025-02307-x |
| Related URLs: | |
| Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:233730 |

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