Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas

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 () and Jianjun Zhang ()
Additional contact information
Xin Hu: The University of Texas MD Anderson Cancer Center
Marcos R. Estecio: The University of Texas MD Anderson Cancer Center
Runzhe Chen: The University of Texas MD Anderson Cancer Center
Alexandre Reuben: The University of Texas MD Anderson Cancer Center
Linghua Wang: The University of Texas MD Anderson Cancer Center
Junya Fujimoto: The University of Texas MD Anderson Cancer Center
Jian Carrot-Zhang: Broad Institute of MIT and Harvard
Nicholas McGranahan: Cancer Research United Kingdom-University College London Lung Cancer Centre of Excellence
Lisha Ying: Chinese Academy of Sciences
Junya Fukuoka: Nagasaki University Graduate School of Biomedical Sciences
Chi-Wan Chow: The University of Texas MD Anderson Cancer Center
Hoa H. N. Pham: Nagasaki University Graduate School of Biomedical Sciences
Myrna C. B. Godoy: The University of Texas MD Anderson Cancer Center
Brett W. Carter: The University of Texas MD Anderson Cancer Center
Carmen Behrens: The University of Texas MD Anderson Cancer Center
Jianhua Zhang: The University of Texas MD Anderson Cancer Center
Mara B. Antonoff: The University of Texas MD Anderson Cancer Center
Boris Sepesi: The University of Texas MD Anderson Cancer Center
Yue Lu: The University of Texas MD Anderson Cancer Center
Harvey I. Pass: New York University Langone Medical Center
Humam Kadara: The University of Texas MD Anderson Cancer Center
Paul Scheet: The University of Texas MD Anderson Cancer Center
Ara A. Vaporciyan: The University of Texas MD Anderson Cancer Center
John V. Heymach: The University of Texas MD Anderson Cancer Center
Ignacio I. Wistuba: The University of Texas MD Anderson Cancer Center
J. Jack Lee: The University of Texas MD Anderson Cancer Center
P. Andrew Futreal: The University of Texas MD Anderson Cancer Center
Dan Su: Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)
Jean-Pierre J. Issa: Coriell Institute for Medical Research
Jianjun Zhang: The University of Texas MD Anderson Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-20907-z

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