Functional annotation of noncoding mutations in cancer

Area of Science:

• Genomics
• Cancer Biology
• Bioinformatics

Background:

• Noncoding sequences constitute the majority of somatic mutations in cancer genomes.
• Mutations in regulatory elements can influence gene expression and contribute to cancer development.

Purpose of the Study:

• To systematically screen and prioritize regulatory mutations across a large cancer genome dataset.
• To investigate the potential roles of these mutations in cancer progression.

Main Methods:

• Analysis of somatic mutations in 2,515 whole cancer genomes from the Pan-Cancer Analysis of Whole Genomes cohort.
• Identification and prioritization of mutations within regulatory elements.
• Assessment of mutation enrichment patterns, including association with specific mutational signatures and transcription factor binding sites.

Main Results:

• Significant enrichment of regulatory mutations near CpG sites within CCAAT/Enhancer Binding Protein β recognition sites, particularly associated with the deamination signature.
• Identification of 5,749 mutated regulatory elements across 1,844 tumor samples.
• An average of six regulatory mutations per tumor, with 5.5% of samples exhibiting 20 or more such mutations.
• Enrichment of cancer-related pathways in genes located near mutated regulatory elements.

Conclusions:

• Regulatory mutations play a significant role in cancer genomes, affecting gene regulation and potentially driving cancer.
• The study provides a comprehensive catalog of mutated regulatory elements and highlights their association with specific mutational processes and transcription factor binding sites.
• These findings offer insights into the functional impact of noncoding mutations in cancer.