Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas.

Abstract

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.

• Authors: Xin Hu, Marcos R Estecio, Runzhe Chen, Alexandre Reuben, Linghua Wang, Junya Fujimoto, Jian Carrot-Zhang, Nicholas McGranahan, Lisha Ying, Junya Fukuoka, Chi-Wan Chow, Hoa H N Pham, Myrna C B Godoy, Brett W Carter, Carmen Behrens, Jianhua Zhang, Mara B Antonoff, Boris Sepesi, Yue Lu, Harvey I Pass, Humam Kadara, Paul Scheet, Ara A Vaporciyan, John V Heymach, Ignacio I Wistuba, J Jack Lee, P Andrew Futreal, Dan Su, Jean-Pierre J Issa, Jianjun Zhang
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 687 (01 29 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 33514726 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Topics

• Adenocarcinoma of Lung (genetics, mortality, pathology)
• Adult
• Aged
• Aged, 80 and over
• Carcinogenesis (genetics)
• Chromosomal Instability
• DNA Copy Number Variations
• DNA Methylation (genetics)
• Disease Progression
• Epigenome (genetics)
• Female
• Genetic Heterogeneity
• Humans
• Hyperplasia (genetics, pathology)
• Lung (pathology)
• Lung Neoplasms (genetics, mortality, pathology)
• Male
• Middle Aged
• Mutagenesis
• Mutation Rate
• Precancerous Conditions (genetics, pathology)
• Survival Analysis
• Tumor Microenvironment (genetics)