DNA Methylation Profiling Identifies Subgroups of Lung Adenocarcinoma with Distinct Immune Cell Composition, DNA Methylation Age, and Clinical Outcome.

Abstract

PURPOSE:

Lung adenocarcinoma (LUAD) is a clinically heterogeneous disease, which is highlighted by the unpredictable recurrence in low-stage tumors and highly variable responses observed in patients treated with immunotherapies, which cannot be explained by mutational profiles. DNA methylation-based classification and understanding of microenviromental heterogeneity may allow stratification into clinically relevant molecular subtypes of LUADs.

EXPERIMENTAL DESIGN:

We characterize the genome-wide DNA methylation landscape of 88 resected LUAD tumors. Exome sequencing focusing on a panel of cancer-related genes was used to genotype these adenocarcinoma samples. Bioinformatic and statistical tools, the immune cell composition, DNA methylation age (DNAm age), and DNA methylation clustering were used to identify clinically relevant subgroups.

RESULTS:

Deconvolution of DNA methylation data identified immunologically hot and cold subsets of LUADs. In addition, concurrent factors were analyzed that could affect the immune microenvironment, such as smoking history, ethnicity, or presence of KRAS or TP53 mutations. When the DNAm age was calculated, a lower DNAm age was correlated with the presence of a set of oncogenic drivers, poor overall survival, and specific immune cell populations. Unsupervised DNA methylation clustering identified six molecular subgroups of LUAD tumors with distinct clinical and microenvironmental characteristics.

CONCLUSIONS:

Our results demonstrate that DNA methylation signatures can stratify LUAD into clinically relevant subtypes, and thus such classification of LUAD at the time of resection may lead to better methods in predicting tumor recurrence and therapy responses.

• Authors: Kayla Guidry, Varshini Vasudevaraja, Kristen Labbe, Hussein Mohamed, Jonathan Serrano, Brett W Guidry, Michael DeLorenzo, Hua Zhang, Jiehui Deng, Soumyadip Sahu, Christina Almonte, Andre L Moreira, Aristotelis Tsirigos, Thales Papagiannakopoulos, Harvey Pass, Matija Snuderl, Kwok-Kin Wong
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 28 Issue 17 Pg. 3824-3835 (09 01 2022) ISSN: 1557-3265 [Electronic] United States
• PMID: 35802677 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2022 American Association for Cancer Research.

Topics

• Adenocarcinoma (pathology)
• Adenocarcinoma of Lung (genetics)
• DNA Methylation
• Humans
• Lung Neoplasms (pathology)
• Mutation
• Tumor Microenvironment