DNA methylation cooperates with genomic alterations during non-small cell lung cancer evolution More about Open Access at the Crick
Authors list
Francisco Gimeno-Valiente Carla Castignani Elizabeth Larose Cadieux Nana Mensah Xiaohong Liu Kezhong Chen Olga Chervova Takahiro Karasaki Clare Weeden Corentin Richard Siqi Lai Carlos Martínez-Ruiz Emilia Lim Alexander Frankell Tom Watkins Georgia Stavrou Ieva Usaite Wei-Ting Lu Daniele Marinelli Sadegh Saghafinia Gareth Wilson Pawan Dhami Heli Vaikkinen Jonathan Steif Selvaraju Veeriah Rob Hynds Martin Hirst Crispin Hiley Andrew Feber Özgen Deniz Mariam Jamal-Hanjani Nicholas McGranahan TRACERx Consortium Stephan Beck Jonas Demeulemeester Miljana Tanić Charles Swanton Peter Van Loo Nnennaya Kanu
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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.
Journal details
Journal
Nature Genetics
Volume
57
Issue number
9
Pages
2226-2237
Available online
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10.1038/s41588-025-02307-x
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Europe PubMed Central
40931149
Pubmed
40931149
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