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Updated: Nov 10, 2025
Author Spotlight: Impact of Intergenic Interactions on Disease-Identifying Dark Biomarkers
Published on: March 1, 2024
Pan-Cancer Analysis of Human Kinome Gene Expression and Promoter DNA Methylation Identifies Dark Kinase Biomarkers in
Siddesh Southekal1, Nitish Kumar Mishra1, Chittibabu Guda1
1Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198-5805, USA.
Abstract:
Kinases are a group of intracellular signaling molecules that play critical roles in various biological processes. Even though kinases comprise one of the most well-known therapeutic targets, many have been understudied and therefore warrant further investigation. DNA methylation is one of the key epigenetic regulators that modulate gene expression. In this study, the human kinome's DNA methylation and gene expression patterns were analyzed using the level-3 TCGA data for 32 cancers. Unsupervised clustering based on kinome data revealed the grouping of cancers based on their organ level and tissue type. We further observed significant differences in overall kinase methylation levels (hyper- and hypomethylation) between the tumor and adjacent normal samples from the same tissue. Methylation expression quantitative trait loci (meQTL) analysis using kinase gene expression with the corresponding methylated probes revealed a highly significant and mostly negative association (~92%) within 1.5 kb from the transcription start site (TSS). Several understudied (dark) kinases (PKMYT1, PNCK, BRSK2, ERN2, STK31, STK32A, and MAPK4) were also identified with a significant role in patient survival. This study leverages results from multi-omics data to identify potential kinase markers of prognostic and diagnostic importance and further our understanding of kinases in cancer.
Insights
This study analyzed DNA methylation and gene expression in the human kinome across 32 cancers. Key findings reveal cancer subtypes and identify understudied kinases with prognostic significance for cancer survival.
Area of Science:
- Genomics
- Epigenetics
- Cancer Biology
Background:
- Kinases are crucial intracellular signaling molecules and established therapeutic targets.
- Many kinases remain understudied, necessitating further investigation into their roles.
- DNA methylation is a key epigenetic regulator influencing gene expression.
Purpose of the Study:
- To analyze DNA methylation and gene expression patterns across the human kinome in 32 cancers.
- To identify potential diagnostic and prognostic kinase markers.
- To deepen the understanding of kinase involvement in cancer.
Main Methods:
- Utilized level-3 TCGA data for 32 cancers.
- Performed unsupervised clustering based on kinome data.
- Conducted methylation expression quantitative trait loci (meQTL) analysis.
Main Results:
- Clustering grouped cancers by organ level and tissue type.
- Significant differences in kinase methylation (hyper- and hypomethylation) were observed between tumor and normal tissues.
- A strong, predominantly negative association was found between kinase gene expression and methylation probes near the transcription start site (TSS).
- Several understudied kinases were identified as significant for patient survival.
Conclusions:
- Multi-omics data analysis identified potential kinase markers for cancer prognosis and diagnosis.
- The study enhances understanding of kinase roles in cancer development and progression.
- Understudied kinases represent promising targets for future research and therapeutic strategies.
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