Background: Though the development of targeted cancer drugs continues to accelerate, doctors still lack reliable methods for predicting patient response to standard-of-care therapies for most cancers. DNA methylation has been implicated in tumor drug response and is a promising source of predictive biomarkers of drug efficacy, yet the relationship between drug efficacy and DNA methylation remains largely unexplored. Method: In this analysis, we performed log-rank survival analyses on patients grouped by cancer and drug exposure to find CpG sites where binary methylation status is associated with differential survival in patients treated with a specific drug but not in patients with the same cancer who were not exposed to that drug. We also clustered these drug-specific CpG sites based on co-methylation among patients to identify broader methylation patterns that may be related to drug efficacy, which we investigated for transcription factor binding site enrichment using gene set enrichment analysis. Results: We identified CpG sites that were drug-specific predictors of survival in 38 cancer-drug patient groups across 15 cancers and 20 drugs. These included 11 CpG sites with similar drug-specific survival effects in multiple cancers. We also identified 76 clusters of CpG sites with stronger associations with patient drug response, many of which contained CpG sites in gene promoters containing transcription factor binding sites. Conclusion: These findings are promising biomarkers of drug response for a variety of drugs and contribute to our understanding of drug-methylation interactions in cancer. Investigation and validation of these results could lead to the development of targeted co-therapies aimed at manipulating methylation in order to improve efficacy of commonly used therapies and could improve patient survival and quality of life by furthering the effort toward drug response prediction.
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Statistical and bioinformatic analysis of hemimethylation patterns in non-small cell lung cancer
Abstract Background DNA methylation is an epigenetic event involving the addition of a methyl-group to a cytosine-guanine base pair (i.e., CpG site). It is associated with different cancers. Our research focuses on studying non-small cell lung cancer hemimethylation, which refers to methylation occurring on only one of the two DNA strands. Many studies often assume that methylation occurs on both DNA strands at a CpG site. However, recent publications show the existence of hemimethylation and its significant impact. Therefore, it is important to identify cancer hemimethylation patterns. Methods In this paper, we use the Wilcoxon signed rank test to identify hemimethylated CpG sites based on publicly available non-small cell lung cancer methylation sequencing data. We then identify two types of hemimethylated CpG clusters, regular and polarity clusters, and genes with large numbers of hemimethylated sites. Highly hemimethylated genes are then studied for their biological interactions using available bioinformatics tools. Results In this paper, we have conducted the first-ever investigation of hemimethylation in lung cancer. Our results show that hemimethylation does exist in lung cells either as singletons or clusters. Most clusters contain only two or three CpG sites. Polarity clusters are much shorter than regular clusters and appear less frequently. The majority of clusters found in tumor samples have no overlap with clusters found in normal samples, and vice versa. Several genes that are known to be associated with cancer are hemimethylated differently between the cancerous and normal samples. Furthermore, highly hemimethylated genes exhibit many different interactions with other genes that may be associated with cancer. Hemimethylation has diverse patterns and frequencies that are comparable between normal and tumorous cells. Therefore, hemimethylation may be related to both normal and tumor cell development. Conclusions Our research has identified CpG clusters and genes that are hemimethylated in normal and lung tumor samples. Due to the potential impact of hemimethylation on gene expression and cell function, these clusters and genes may be important to advance our understanding of the development and progression of non-small cell lung cancer.
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- Award ID(s):
- 1757233
- NSF-PAR ID:
- 10290093
- Date Published:
- Journal Name:
- BMC Cancer
- Volume:
- 21
- Issue:
- 1
- ISSN:
- 1471-2407
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1186/s12885-021-07990-7
