Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas.
Adenocarcinoma of Lung
/ genetics
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
Lung
/ pathology
Lung Neoplasms
/ genetics
Male
Middle Aged
Mutagenesis
Mutation Rate
Precancerous Conditions
/ genetics
Survival Analysis
Tumor Microenvironment
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
29 01 2021
29 01 2021
Historique:
received:
14
07
2020
accepted:
17
12
2020
entrez:
30
1
2021
pubmed:
31
1
2021
medline:
20
2
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33514726
doi: 10.1038/s41467-021-20907-z
pii: 10.1038/s41467-021-20907-z
pmc: PMC7846738
doi:
Types de publication
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.
Langues
eng
Sous-ensembles de citation
IM
Pagination
687Subventions
Organisme : NCI NIH HHS
ID : P50 CA070907
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA234629
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA214195
Pays : United States
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