Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas

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 hyper...

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Vydáno v:	Nature communications Ročník 12; číslo 1; s. 687 - 13
Hlavní autoři:	Hu, Xin, Estecio, Marcos R., Chen, Runzhe, Reuben, Alexandre, Wang, Linghua, Fujimoto, Junya, Carrot-Zhang, Jian, McGranahan, Nicholas, Ying, Lisha, Fukuoka, Junya, Chow, Chi-Wan, Pham, Hoa H. N., Godoy, Myrna C. B., Carter, Brett W., Behrens, Carmen, Zhang, Jianhua, Antonoff, Mara B., Sepesi, Boris, Lu, Yue, Pass, Harvey I., Kadara, Humam, Scheet, Paul, Vaporciyan, Ara A., Heymach, John V., Wistuba, Ignacio I., Lee, J. Jack, Futreal, P. Andrew, Su, Dan, Issa, Jean-Pierre J., Zhang, Jianjun
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 29.01.2021 Nature Publishing Group Nature Portfolio
Témata:	45 45/23 631/208/177 631/67/1612/1350 631/67/2329 631/67/69 Adenocarcinoma Adenocarcinoma of Lung - genetics Adenocarcinoma of Lung - mortality Adenocarcinoma of Lung - pathology Adult Aged Aged, 80 and over Bisulfite Carcinogenesis Carcinogenesis - genetics Carcinogens CD8 antigen Chromosomal Instability Convolution Copy number Deoxyribonucleic acid Disease Progression DNA DNA Copy Number Variations DNA methylation DNA Methylation - genetics Epigenome - genetics Evolution Evolution & development Female Genetic Heterogeneity Genomic instability Heterogeneity Humanities and Social Sciences Humans Hyperplasia Hyperplasia - genetics Hyperplasia - pathology Immunoregulation Immunosuppression Lesions Lung - pathology Lung cancer Lung Neoplasms - genetics Lung Neoplasms - mortality Lung Neoplasms - pathology Lungs Lymphocytes Lymphocytes T Male Metastases Microenvironments Middle Aged multidisciplinary Mutagenesis Mutation Mutation Rate Phylogeny Precancerous Conditions - genetics Precancerous Conditions - pathology Science Science (multidisciplinary) Survival Analysis Tumor Microenvironment - genetics Tumors
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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. It is known that invasive lung adenocarcinomas evolve from pre-cancerous dysplastic lesions. In this study, the authors show that evolution of pre-cancerous lesions is accompanied by DNA methylation alterations, and that global hypomethylation correlates with immune infiltration, mutational burden and copy number alterations.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-021-20907-z