Zhao, X., Yang, M., Fan, J. et al. (45 more authors) (2024) Identification of genetically predicted DNA methylation markers associated with non–small cell lung cancer risk among 34,964 cases and 448,579 controls. Cancer, 130 (6). pp. 913-926. ISSN 0008-543X
Abstract
Background
Although the associations between genetic variations and lung cancer risk have been explored, the epigenetic consequences of DNA methylation in lung cancer development are largely unknown. Here, the genetically predicted DNA methylation markers associated with non–small cell lung cancer (NSCLC) risk by a two-stage case-control design were investigated.
Methods
The genetic prediction models for methylation levels based on genetic and methylation data of 1595 subjects from the Framingham Heart Study were established. The prediction models were applied to a fixed-effect meta-analysis of screening data sets with 27,120 NSCLC cases and 27,355 controls to identify the methylation markers, which were then replicated in independent data sets with 7844 lung cancer cases and 421,224 controls. Also performed was a multi-omics functional annotation for the identified CpGs by integrating genomics, epigenomics, and transcriptomics and investigation of the potential regulation pathways.
Results
Of the 29,894 CpG sites passing the quality control, 39 CpGs associated with NSCLC risk (Bonferroni-corrected p ≤ 1.67 × 10−6) were originally identified. Of these, 16 CpGs remained significant in the validation stage (Bonferroni-corrected p ≤ 1.28 × 10−3), including four novel CpGs. Multi-omics functional annotation showed nine of 16 CpGs were potentially functional biomarkers for NSCLC risk. Thirty-five genes within a 1-Mb window of 12 CpGs that might be involved in regulatory pathways of NSCLC risk were identified.
Conclusions
Sixteen promising DNA methylation markers associated with NSCLC were identified. Changes of the methylation level at these CpGs might influence the development of NSCLC by regulating the expression of genes nearby.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2023 American Cancer Society. |
Keywords: | DNA methylation; association study; gene expression; genetic prediction; non-small cell lung cancer risk; Adult; Humans; Carcinoma, Non-Small-Cell Lung; DNA Methylation; Lung Neoplasms; Genome-Wide Association Study; Epigenesis, Genetic; Biomarkers; CpG Islands |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 23 Aug 2024 13:50 |
Last Modified: | 23 Aug 2024 13:50 |
Status: | Published |
Publisher: | Wiley |
Refereed: | Yes |
Identification Number: | 10.1002/cncr.35130 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:216438 |