Faculty, Staff and Student Publications

Publication Date

9-1-2025

Journal

Nature Genetics

DOI

10.1038/s41588-025-02307-x

PMID

40931149

PMCID

PMC12425823

PubMedCentral® Posted Date

9-10-2025

PubMedCentral® Full Text Version

Post-print

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.

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

Published Open-Access

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