Pan-cancer noncoding genomic analysis identifies functional CDC20 promoter mutation hotspots

Area of Science:

• Genomics
• Cancer Biology
• Molecular Genetics

Background:

• Noncoding DNA comprises over 98% of the human genome, yet its role as a driver in cancer remains underexplored compared to coding DNA.
• Identifying functional noncoding mutations is challenging due to distinct mutation patterns and functions of noncoding DNA.
• The CDC20 gene plays a crucial role in cell division and is often dysregulated in various cancers.

Purpose of the Study:

• To investigate functional noncoding mutations in cancer by analyzing whole-genome mutation data.
• To identify specific noncoding alterations that impact protein factor binding and gene regulation.
• To elucidate the mechanism by which noncoding mutations contribute to cancer development, focusing on the CDC20 gene.

Main Methods:

• Pan-cancer whole genome mutation analysis was performed to screen for recurrent noncoding mutations.
• Investigated mutations in the promoter region of the CDC20 gene.
• Assessed the impact of these mutations on the binding of the ELK4 transcription repressor and subsequent CDC20 gene expression.

Main Results:

• Recurrent hotspot mutations were identified in the promoter of the CDC20 gene across multiple cancer types.
• These CDC20 promoter mutations were found to disrupt the binding of the ELK4 transcription repressor.
• The disruption of ELK4 binding leads to the transcriptional up-regulation of the CDC20 gene, contributing to its deregulation in cancer.

Conclusions:

• A novel mechanism for CDC20 gene deregulation in human cancers involving functional noncoding mutations in its promoter has been identified.
• The study highlights the importance of noncoding DNA alterations as potential drivers of cancer.
• Findings provide a foundation for developing function-based pipelines for discovering noncoding cancer drivers.