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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Published in:Nature communications Vol. 12; no. 1; pp. 687 - 13
Main Authors: 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
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 29.01.2021
Nature Publishing Group
Nature Portfolio
Subjects:
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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Summary: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.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-20907-z