伦敦大学学院癌症研究所Nnennaya Kanu课题组揭示了在非小细胞肺癌的进化过程中，DNA甲基化与基因组改变密切相关。相关论文发表在2025年9月10日出版的《自然—遗传学》杂志上。

为了探讨这一点，研究组对来自TRACERx研究的59名非小细胞肺癌患者的217个肿瘤和匹配的正常区域进行了减少代表性的亚硫酸氢盐测序，以反卷积肿瘤甲基化。研究团队利用DNA和RNA测序数据开发了两个综合进化分析指标。肿瘤内甲基化距离量化肿瘤内DNA甲基化异质性。MR/MN根据调节性（MR）和非调节性（MN） CpGs的高甲基化率对基因进行分类，以确定表现出复发性功能性高甲基化的驱动基因。研究人员确定了与邻近癌基因共同扩增的必要基因的DNA甲基化相关剂量补偿。该研究团队提出了两种互补的机制，这些机制收敛于拷贝数改变影响的染色质，以经历表观遗传等效的变构活性转变。正选择下的高甲基化驱动基因可能为患者的治疗分层开辟道路。

研究人员表示，几乎在所有人类癌症中都有异常DNA甲基化的描述，但其与肿瘤进化过程中基因组改变的相互作用却知之甚少。

附：英文原文

Title: DNA methylation cooperates with genomic alterations during non-small cell lung cancer evolution

Author: Gimeno-Valiente, Francisco, Castignani, Carla, Larose Cadieux, Elizabeth, Mensah, Nana E., Liu, Xiaohong, Chen, Kezhong, Chervova, Olga, Karasaki, Takahiro, Weeden, Clare E., Richard, Corentin, Lai, Siqi, Martnez-Ruiz, Carlos, Lim, Emilia L., Frankell, Alexander M., Watkins, Thomas B. K., Stavrou, Georgia, Usaite, Ieva, Lu, Wei-Ting, Marinelli, Daniele, Saghafinia, Sadegh, Wilson, Gareth A., Dhami, Pawan, Vaikkinen, Heli, Steif, Jonathan, Veeriah, Selvaraju, Hynds, Robert E., Hirst, Martin, Hiley, Crispin, Feber, Andrew, Deniz, zgen, Jamal-Hanjani, Mariam, McGranahan, Nicholas, Beck, Stephan, Demeulemeester, Jonas, Tani, Miljana, Swanton, Charles, Van Loo, Peter, Kanu, Nnennaya

Issue&Volume: 2025-09-10

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.

DOI: 10.1038/s41588-025-02307-x

Source: https://www.nature.com/articles/s41588-025-02307-x