Dataset Information

Genome-wide analysis reveals the association between alternative splicing and DNA methylation across human solid tumors.

ABSTRACT:

Background

Dysregulation of alternative splicing (AS) is a critical signature of cancer. However, the regulatory mechanisms of cancer-specific AS events, especially the impact of DNA methylation, are poorly understood.

Methods

By using The Cancer Genome Atlas (TCGA) SpliceSeq and TCGA data for ten solid tumor types, association analysis was performed to characterize the potential link between cancer-specific AS and DNA methylation. Functional and pathway enrichment analyses were performed, and the protein-protein interaction (PPI) network was constructed with the String website. The prognostic analysis was carried out with multivariate Cox regressions models.

Results

15,818 AS events in 3955 annotated genes were identified across ten solid tumor types. The different DNA methylation patterns between tumor and normal tissues at the corresponding alternative spliced exon boundaries were shown, and 51.3% of CpG sites (CpGs) revealed hypomethylated in tumors. Notably, 607 CpGs were found to be highly correlated with 369 cancer-specific AS events after permutation tests. Among them, the hypomethylated CpGs account for 52.7%, and the number of down-regulated exons was 173. Furthermore, we found 38 AS events in 35 genes could serve as new molecular biomarkers to predict patient survival.

Conclusions

Our study described the relationship between DNA methylation and AS events across ten human solid tumor types and provided new insights into intragenic DNA methylation and exon usage during the AS process.

SUBMITTER: Sun X

PROVIDER: S-EPMC6945449 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

Genome-wide analysis reveals the association between alternative splicing and DNA methylation across human solid tumors.

Sun Xiaohui X Tian Yiping Y Wang Jianming J Sun Zeyuan Z Zhu Yimin Y

BMC medical genomics 20200106 1

<h4>Background</h4>Dysregulation of alternative splicing (AS) is a critical signature of cancer. However, the regulatory mechanisms of cancer-specific AS events, especially the impact of DNA methylation, are poorly understood.<h4>Methods</h4>By using The Cancer Genome Atlas (TCGA) SpliceSeq and TCGA data for ten solid tumor types, association analysis was performed to characterize the potential link between cancer-specific AS and DNA methylation. Functional and pathway enrichment analyses were p ...[more]

PMID: 31906954

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Project description:Gene bodies are the most evolutionarily conserved targets of DNA methylation in eukaryotes. However, the regulatory functions of gene body DNA methylation remain largely unknown. DNA methylation in insects appears to be primarily confined to exons. Two recent studies in Apis mellifera (honeybee) and Nasonia vitripennis (jewel wasp) analyzed transcription and DNA methylation data for one gene in each species to demonstrate that exon-specific DNA methylation may be associated with alternative splicing events. In this study we investigated the relationship between DNA methylation, alternative splicing, and cross-species gene conservation on a genome-wide scale using genome-wide transcription and DNA methylation data.We generated RNA deep sequencing data (RNA-seq) to measure genome-wide mRNA expression at the exon- and gene-level. We produced a de novo transcriptome from this RNA-seq data and computationally predicted splice variants for the honeybee genome. We found that exons that are included in transcription are higher methylated than exons that are skipped during transcription. We detected enrichment for alternative splicing among methylated genes compared to unmethylated genes using fisher's exact test. We performed a statistical analysis to reveal that the presence of DNA methylation or alternative splicing are both factors associated with a longer gene length and a greater number of exons in genes. In concordance with this observation, a conservation analysis using BLAST revealed that each of these factors is also associated with higher cross-species gene conservation.This study constitutes the first genome-wide analysis exhibiting a positive relationship between exon-level DNA methylation and mRNA expression in the honeybee. Our finding that methylated genes are enriched for alternative splicing suggests that, in invertebrates, exon-level DNA methylation may play a role in the construction of splice variants by positively influencing exon inclusion during transcription. The results from our cross-species homology analysis suggest that DNA methylation and alternative splicing are genetic mechanisms whose utilization could contribute to a longer gene length and a slower rate of gene evolution.

Project description:Therapeutic options for the treatment of an increasing variety of cancers have been expanded by the introduction of a new class of drugs, commonly referred to as checkpoint blocking agents, that target the host immune system to positively modulate anti-tumor immune response. Although efficacy of these agents has been linked to a pre-existing level of tumor immune infiltrate, it remains unclear why some patients exhibit deep and durable responses to these agents while others do not benefit. To examine the influence of tumor genetics on tumor immune state, we interrogated the relationship between somatic mutation and copy number alteration with infiltration levels of 7 immune cell types across 40 tumor cohorts in The Cancer Genome Atlas. Levels of cytotoxic T, regulatory T, total T, natural killer, and B cells, as well as monocytes and M2 macrophages, were estimated using a novel set of transcriptional signatures that were designed to resist interference from the cellular heterogeneity of tumors. Tumor mutational load and estimates of tumor purity were included in our association models to adjust for biases in multi-modal genomic data. Copy number alterations, mutations summarized at the gene level, and position-specific mutations were evaluated for association with tumor immune infiltration. We observed a strong relationship between copy number loss of a large region of chromosome 9p and decreased lymphocyte estimates in melanoma, pancreatic, and head/neck cancers. Mutations in the oncogenes PIK3CA, FGFR3, and RAS/RAF family members, as well as the tumor suppressor TP53, were linked to changes in immune infiltration, usually in restricted tumor types. Associations of specific WNT/beta-catenin pathway genetic changes with immune state were limited, but we noted a link between 9p loss and the expression of the WNT receptor FZD3, suggesting that there are interactions between 9p alteration and WNT pathways. Finally, two different cell death regulators, CASP8 and DIDO1, were often mutated in head/neck tumors that had higher lymphocyte infiltrates. In summary, our study supports the relevance of tumor genetics to questions of efficacy and resistance in checkpoint blockade therapies. It also highlights the need to assess genome-wide influences during exploration of any specific tumor pathway hypothesized to be relevant to therapeutic response. Some of the observed genetic links to immune state, like 9p loss, may influence response to cancer immune therapies. Others, like mutations in cell death pathways, may help guide combination therapeutic approaches.

Dataset Information

Genome-wide analysis reveals the association between alternative splicing and DNA methylation across human solid tumors.

Background

Methods

Results

Conclusions

Publications

Genome-wide analysis reveals the association between alternative splicing and DNA methylation across human solid tumors.

Similar Datasets

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