癌症中广泛存在表观遗传改变，可以与基因改变一起影响癌症的进展和治疗结果。为了确定DNA甲基化改变对非小细胞肺癌（NSCLC）病人的肿瘤表型的潜在贡献，我们使用互补性的实验方法甲基化DNA免疫沉淀测序（MeDIP-seq）和甲基化敏感性限制酶消化测序（MRE-seq），对17个原发性NSCLC肿瘤和10个配对的正常肺样本进行了基因组范围的DNA甲基化分析。我们报道了几个基因启动子的反复甲基化改变，其中许多已经与癌症有关，包括FAM83A和SEPT9（低甲基化），以及PCDH7、NKX2-1和SOX17（高甲基化）。虽然许多肿瘤与其配对的正常样本之间的甲基化改变在病人之间存在共享，但是也有些是特定于不同吸烟状况的。例如，从不吸烟者显示了更高比例的低甲基化差异甲基化区域（hypoDMRs）和更多的反复低甲基化启动子，包括与癌症有关的ASPSCR1、TOP2A、DPP9和USP39。启动子之外的改变也是广泛存在且经常反复出现，尤其是重复元素上的甲基化丢失，高度富集于ERV1亚科。反复出现的hypoDMRs富含一些转录因子结合位点，常常是与信号传导和细胞增殖相关的基因。例如，71%的反复发生的启动子hypoDMRs含有一个NKX2-1的结合位点。最后，大多数DMRs位于根据Roadmap Epigenome数据分析的组织中的活性染色质状态内，这表明甲基化改变可能通过适应细胞特异性表达程序而对改变的调控程序做出贡献。 版权所有 © 2023. Elsevier B.V. 出版。

Epigenetic alterations are widespread in cancer and can complement genetic alterations to influence cancer progression and treatment outcome. To determine the potential contribution of DNA methylation alterations to tumor phenotype in non-small cell lung cancer (NSCLC) in both smoker and never-smoker patients, we performed genome-wide profiling of DNA methylation in 17 primary NSCLC tumors and 10 matched normal lung samples using the complementary assays methylation DNA immunoprecipitation (MeDIP-seq) and methylation sensitive restriction enzyme digestion followed by sequencing (MRE-seq). We reported recurrent methylation changes of several gene promoters, many previously implicated in cancer, including FAM83A and SEPT9 (hypomethylation), as well as PCDH7, NKX2-1, and SOX17 (hypermethylation). Although many methylation changes between tumors and their paired normal samples were shared across patients, several were specific to a particular smoking status. For example, never-smokers displayed a greater proportion of hypomethylated differentially methylated regions (hypoDMRs) and a greater number of recurrently hypomethylated promoters, including those of ASPSCR1, TOP2A, DPP9, and USP39, all previously linked to cancer. Changes outside of promoters were also widespread and often recurrent, particularly methylation loss over repetitive elements, highly enriched for ERV1 subfamilies. Recurrent hypoDMRs were enriched for several transcription factor binding motifs, often for genes involved in signaling and cell proliferation. For example, 71% of recurrent promoter hypoDMRs contained a motif for NKX2-1. Finally, the majority of DMRs were located within an active chromatin state in tissues profiled using the Roadmap Epigenome data, suggesting that methylation changes may contribute to altered regulatory programs through the adaptation of cell type-specific expression programs.Copyright © 2023. Published by Elsevier B.V.