Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Nat Commun. 2021 Jan 29;12(1):687. doi: 10.1038/s41467-021-20907-z.
The evolution of DNA methylome and methylation intra-tumor heterogeneity (ITH) during early carcinogenesis of lung adenocarcinoma has not been systematically studied. We perform reduced representation bisulfite sequencing of invasive lung adenocarcinoma and its precursors, atypical adenomatous hyperplasia, adenocarcinoma in situ and minimally invasive adenocarcinoma. We observe gradual increase of methylation aberrations and significantly higher level of methylation ITH in later-stage lesions. The phylogenetic patterns inferred from methylation aberrations resemble those based on somatic mutations suggesting parallel methylation and genetic evolution. De-convolution reveal higher ratio of T regulatory cells (Tregs) versus CD8 + T cells in later-stage diseases, implying progressive immunosuppression with neoplastic progression. Furthermore, increased global hypomethylation is associated with higher mutation burden, copy number variation burden and AI burden as well as higher Treg/CD8 ratio, highlighting the potential impact of methylation on chromosomal instability, mutagenesis and tumor immune microenvironment during early carcinogenesis of lung adenocarcinomas.
在肺腺癌早期癌变过程中，DNA 甲基组和甲基化肿瘤内异质性（ITH）的演变尚未得到系统研究。我们对浸润性肺腺癌及其前体，非典型腺瘤性增生、原位腺癌和微浸润性腺癌进行了简化代表性重亚硫酸盐测序。我们观察到甲基化异常逐渐增加，晚期病变的甲基化 ITH 水平显著升高。基于甲基化异常推断的系统发育模式类似于基于体细胞突变的模式，提示甲基化和遗传进化并行。去卷积显示，晚期疾病中 T 调节细胞（Tregs）与 CD8+T 细胞的比例更高，这意味着随着肿瘤的进展，免疫抑制逐渐增强。此外，全基因组低甲基化与更高的突变负担、拷贝数变异负担和 AI 负担以及更高的 Treg/CD8 比例相关，这突出了甲基化在肺腺癌早期癌变过程中对染色体不稳定性、致突变性和肿瘤免疫微环境的潜在影响。
