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DNA methylome and transcriptome landscapes of cancer-associated fibroblasts reveal a hidden smoking-associated malignancy index of tumor microenvironment (Illumina 2)

ABSTRACT: Unlike the better-studied aberrant epigenome in the tumor, the clinicopathologic impact of DNA methylation in the tumor microenvironment (TME), especially cancer-associated fibroblast (CAF), remains elusive. CAFs exhibit profound patient-to-patient tumorigenic heterogeneity. However, molecular characterization on patient-derived CAFs with follow-up data is limited, hindering the progress of targeting CAFs in precision oncology. Here we developed a robust and efficient methylome/transcriptome co-analysis system to comprehensively profile CAFs and paired normal fibroblasts (NFs) from non-small-cell lung cancer patients (NSCLC) and revealed a hidden smoking-associated DNA methylation index that quantifies the malignancy level of TME. Out of 14,781 NF/CAF differentially methylated CpG sites, 3,707 (25%) showed higher methylation changes in ever-smokers than non-smokers. Further integrative analysis pinpointed to a specific subset of 54 CpG sites that we used to construct the index for detecting perturbation in CAFs. We applied this index to multiple lung cancer cohorts and confirmed the success in survival prediction. Effective quantification of premalignant status of individual TME adds a new dimension to precision oncology. Although smoking is a well-known risk factor for lung cancer and is associated with methylation in tumor DNA, the epigenomic/transcriptomic perspective on CAF/NF outperforms smoking itself as a clinicopathologic factor for NSCLC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149958 | GEO | 2025/05/01

REPOSITORIES: GEO

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Project description:INTRODUCTION: CDKN2A (p16) inactivation is common in lung cancer and occurs via homozygous deletions, methylation of promoter region, or point mutations. Although p16 promoter methylation has been linked to KRAS mutation and smoking, the associations between p16 inactivation mechanisms and other common genetic mutations and smoking status are still controversial or unknown. METHODS: We determined all three p16 inactivation mechanisms with the use of multiple methodologies for genomic status, methylation, RNA, and protein expression, and correlated them with EGFR, KRAS, STK11 mutations and smoking status in 40 cell lines and 45 tumor samples of primary non-small-cell lung carcinoma. We also performed meta-analyses to investigate the impact of smoke exposure on p16 inactivation. RESULTS: p16 inactivation was the major mechanism of RB pathway perturbation in non-small-cell lung carcinoma, with homozygous deletion being the most frequent method, followed by methylation and the rarer point mutations. Inactivating mechanisms were tightly correlated with loss of mRNA and protein expression. p16 inactivation occurred at comparable frequencies regardless of mutational status of EGFR, KRAS, and STK11, however, the major inactivation mechanism of p16 varied. p16 methylation was linked to KRAS mutation but was mutually exclusive with EGFR mutation. Cell lines and tumor samples demonstrated similar results. Our meta-analyses confirmed a modest positive association between p16 promoter methylation and smoking. CONCLUSION: Our results confirm that all the inactivation mechanisms are truly associated with loss of gene product and identify specific associations between p16 inactivation mechanisms and other genetic changes and smoking status. 40 NSCLC cell lines were profiled on Illumina WG6-V3 expression arrays. They consist of 4 groups of 10 cell lines each: non-smokers with EGFR mutation, non-smokers with EGFR wild-type, smokers with KRAS mutation, smokers with KRAS wild-type. Note that smoking status is not always clear.

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DNA methylome and transcriptome landscapes of cancer-associated fibroblasts reveal a hidden smoking-associated malignancy index of tumor microenvironment (Illumina 2)

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