@article{268af941e6034d4fb133363d1d1906f9,
title = "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.",
author = "Xin Hu and Estecio, {Marcos R.} and Runzhe Chen and Alexandre Reuben and Linghua Wang and Junya Fujimoto and Jian Carrot-Zhang and Nicholas McGranahan and Lisha Ying and Junya Fukuoka and Chow, {Chi Wan} and Pham, {Hoa H.N.} and Godoy, {Myrna C.B.} and Carter, {Brett W.} and Carmen Behrens and Jianhua Zhang and Antonoff, {Mara B.} and Boris Sepesi and Yue Lu and Pass, {Harvey I.} and Humam Kadara and Paul Scheet and Vaporciyan, {Ara A.} and Heymach, {John V.} and Wistuba, {Ignacio I.} and Lee, {J. Jack} and Futreal, {P. Andrew} and Dan Su and Issa, {Jean Pierre J.} and Jianjun Zhang",
note = "Funding Information: Jianjun Zhang reports research funding from Merck, Johnson & Johnson, and consultant fees from BMS, Johnson & Johnson, AstraZeneca, Geneplus, OrigMed, Inno-vent outside the submitted work. J.V.H. reports research funding from AstraZeneca, GlaxoSmithKline, and Spectrum; consultant fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Catalyst, EMD Serono, Foundation Medicine, Hengrui Therapeutics, Genentech, GSK, Guardant Health, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, Seattle Genetics, Spectrum, and Takeda; licensing fees from Spectrum. I.I.W. reports Honoraria from Genentech/Roche, Bayer, Bristol-Myers Squibb, Astra Zeneca/Medimmune, Pfizer, HTG Molecular, Asuragen, Merck, GlaxoSmithKline, Guardant Health, Oncocyte, Flame, and MSD; Research support from Genentech, Oncoplex, HTG Molecular, DepArray, Merck, Bristol-Myers Squibb, Medimmune, Adaptive, Adaptimmune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, lovance, 4D, Novartis, and Akoya. H.K. reports funding from Johnson & Johnson and from Janssen Pharmaceuticals. B.S. reports consultant fees from BMS. The other authors declare neither financial nor non-financial interests in the submitted work. Funding Information: This study was supported by the MD Anderson Khalifa Scholar Award, the National Cancer Institute of the National Institute of Health Research Project Grant (R01CA234629-01), the AACR-Johnson & Johnson Lung Cancer Innovation Science Grant (18-90-52-ZHAN), the MD Anderson Physician Scientist Program, the MD Anderson Lung Cancer Moon Shot Program, Sabin Family Foundation Award, Duncan Family Institute Cancer Prevention Research Seed Funding Program, The University of Texas MD Anderson Cancer Center Pre-Cancer Atlas Project, EDRN U01 (U01CA214195), the Cancer Prevention and Research Institute of Texas Multi-Investigator Research Award grant (RP160668) and the UT Lung Specialized Programs of Research Excellence Grant (P50CA70907). We thank MD Anderson Cancer Center{\textquoteright}s Epigenomics Profiling Core and its Science Park Next-Generation Sequencing Core (CPRIT Core Facility RP120348) for performing RRBS profiling. We also thank Sally Boyd, Jinzhen Chen, and Rong Yao, Stan Bujnowski, Eric Sisson for providing excellent technical support for high-performance cluster resources, and Joe Munch from Scientific Publications in MD Anderson{\textquoteright}s Research Medical Library for editing the manuscript. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
day = "1",
doi = "10.1038/s41467-021-20907-z",
language = "English (US)",
volume = "12",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}