DNA methylome and transcriptome landscapes of cancer-associated fibroblasts reveal a smoking-associated malignancy index
Journal
The Journal of clinical investigation
Date Issued
2021-07-06
Author(s)
Ho, Hao
Li, Jia-Hua
Wu, Ming-Fang
Wang, Hsu-Chieh
Yeh, Hsiang-Yuan
Li, Ker-Chau
Abstract
Unlike the better-studied aberrant epigenome in the tumor, the clinicopathologic impact of DNA methylation in the tumor microenvironment (TME), especially the contribution from cancer-associated fibroblast (CAF), remains elusive. CAFs exhibit profound patient-to-patient tumorigenic heterogeneity. We ask whether such heterogeneity may be exploited to quantify the level of TME malignancy or not. We developed a robust and efficient methylome/transcriptome co-analysis system for CAFs and paired normal fibroblasts (NFs) from non-small-cell lung cancer patients. We found 14,781 CpG sites of CAF/NF differential methylation, of which 3,707 sites showed higher methylation changes in ever-smokers than in non-smokers. Concomitant CAF/NF differential gene expression analysis pinpointed to a subset of 54 smoking-associated CpG sites with strong methylation-regulated gene expression. A methylation index that summarizes the beta-values of these CpGs was built for NF/CAF discrimination (MIND) with high sensitivity and specificity. The potential of MIND in detecting pre-malignancy across individual patients was shown. MIND succeeded in predicting tumor recurrence in multiple lung cancer cohorts without reliance on patient survival data, suggesting that the malignancy level of TME may be effectively graded by this index. Precision TME grading may provide additional pathological information to guide cancer prognosis and open up more options in personalized medicine.
Subjects
Epigenetics; Genetics; Lung cancer; Oncology
SDGs
Other Subjects
CD36 antigen; collagen type 11; epidermal growth factor receptor; epithelial cell adhesion molecule; phosphatidylinositol 3 kinase; protein kinase B; Thy 1 membrane glycoprotein; transcriptome; transforming growth factor beta; transcriptome; A-549 cell line; adult; Article; cancer associated fibroblast; cancer survival; clinical article; cohort analysis; controlled study; DNA methylation; female; flow cytometry; gene expression; high throughput sequencing; human; human cell; immunofluorescence; male; methylome; non small cell lung cancer; nucleotide sequence; personalized medicine; Pi3K/Akt signaling; precancer; pyrosequencing; real time polymerase chain reaction; sensitivity and specificity; smoking; TGF beta signaling; tumor microenvironment; tumor recurrence; Youden index; adverse event; aged; cancer associated fibroblast; CpG island; gene expression regulation; genetics; lung tumor; metabolism; middle aged; non small cell lung cancer; pathology; prognosis; smoking; tumor cell culture; very elderly; Adult; Aged; Aged, 80 and over; Cancer-Associated Fibroblasts; Carcinoma, Non-Small-Cell Lung; CpG Islands; DNA Methylation; Epigenome; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Smoking; Transcriptome; Tumor Cells, Cultured; Tumor Microenvironment
Type
journal article