Karlow Jennifer A, Pehrsson Erica C, Xing Xiaoyun, Watson Mark, Devarakonda Siddhartha, Govindan Ramaswamy, Wang Ting
Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Genomics Proteomics Bioinformatics. 2023 Oct;21(5):991-1013. doi: 10.1016/j.gpb.2023.03.006. Epub 2023 Sep 22.
Epigenetic alterations are widespread in cancer and can complement genetic alterations to influence cancer progression and treatment outcome. To determine the potential contribution of DNAmethylation 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, methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylation sensitive restriction enzyme sequencing (MRE-seq). We reported recurrent methylation changes in the promoters of several genes, 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 Epigenomics data, suggesting that methylation changes may contribute to altered regulatory programs through the adaptation of cell type-specific expression programs.
表观遗传改变在癌症中广泛存在，并且可以补充基因改变以影响癌症进展和治疗结果。为了确定DNA甲基化改变对吸烟者和从不吸烟者非小细胞肺癌（NSCLC）肿瘤表型的潜在贡献，我们使用甲基化DNA免疫沉淀测序（MeDIP-seq）和甲基化敏感限制酶测序（MRE-seq）这两种互补检测方法，对17例原发性NSCLC肿瘤和10例匹配的正常肺样本进行了全基因组DNA甲基化分析。我们报告了几个基因启动子中反复出现的甲基化变化，其中许多基因先前已被证明与癌症有关，包括FAM83A和SEPT9（低甲基化），以及PCDH7、NKX2-1和SOX17（高甲基化）。尽管肿瘤与其配对的正常样本之间的许多甲基化变化在患者中是共有的，但也有一些变化特定于特定的吸烟状态。例如，从不吸烟者表现出更大比例的低甲基化差异甲基化区域（hypoDMRs）和更多反复出现的低甲基化启动子，包括ASPSCR1、TOP2A、DPP9和USP39的启动子，这些基因先前均与癌症有关。启动子之外的变化也很普遍且经常反复出现，特别是在重复元件上的甲基化缺失，ERV1亚家族高度富集。反复出现的hypoDMRs富含几种转录因子结合基序，通常与信号传导和细胞增殖相关的基因有关。例如，71%的反复出现的启动子hypoDMRs包含NKX2-1的基序。最后，在使用路线图表观基因组学数据进行分析的组织中，大多数DMRs位于活跃的染色质状态内，这表明甲基化变化可能通过适应细胞类型特异性表达程序来促成调节程序的改变。
