Cis-regulatory mutations with driver hallmarks in major cancers

Area of Science:

• Genomics
• Cancer Biology
• Bioinformatics

Background:

• Complete tumor genome sequences are available, but identifying disease-causing non-coding mutations remains a challenge.
• Only a limited number of validated non-coding driver mutations have been identified to date.

Purpose of the Study:

• To identify somatic non-coding mutations that affect gene expression in cis.
• To characterize the functional impact and hallmarks of non-coding driver mutations.

Main Methods:

• Integration of whole-genome sequencing, genetic data, and allele-specific gene expression data from The Cancer Genome Atlas (TCGA).
• Identification and clustering of somatic non-coding mutations within cis-regulatory elements.
• Analysis of mutation impact on transcription factor binding motifs and gene expression.

Main Results:

• Identified 320 somatic non-coding mutations affecting gene expression in cis (FDR<0.25).
• These mutations cluster in 47 cis-regulatory elements, modulating gene expression via diverse mechanisms.
• Mutations preferentially disrupt transcription factor binding motifs and are associated with selective advantage, increased oncogene, and decreased tumor suppressor expression.

Conclusions:

• Discovered a significant number of somatic non-coding mutations with potential driver roles in cancer.
• These non-coding mutations exhibit key features of drivers, impacting gene regulation and cellular fitness.
• Provides a foundation for further investigation into non-coding mutations as therapeutic targets.