Mutation pattern is an influential factor on functional mutation rates in cancer

Area of Science:

• Genomics
• Cancer Biology
• Bioinformatics

Background:

• Mutation rates significantly vary across cancer genomes and impact tumorigenesis.
• The functional potential and distribution of mutations remain incompletely understood.
• Investigating genomic features influencing mutation patterns is crucial for understanding cancer development.

Purpose of the Study:

• To identify genomic features that affect cancer mutation patterns.
• To assess the functional importance of mutation patterns in cancer.
• To explore the relationship between mutation density and the distribution of functional and disease-causing variants.

Main Methods:

• Intersected somatic mutations and SNPs from various cancers with 54 genomic features.
• Computed mutation and SNP densities within 1-Mb windows.
• Developed random forest models (CSM and SNP) to predict mutation densities.
• Analyzed model scores against predicted functional and disease-causing variants.

Main Results:

• Identified diverse genomic features (replication time, transcription, histone marks, regulatory elements) influencing local mutation rates.
• Repressive histone marks, replication time, and promoters were key for the somatic mutation model.
• Recombination rate and chromatin organization were most important for the SNP model.
• Low mutation regions exhibited higher densities of deleterious coding mutations, non-coding variants, functional regions, and disease-causing variants.

Conclusions:

• Somatic mutation densities exhibit substantial variation across the cancer genome.
• Mutation frequency serves as a key indicator of functional impact.
• Mutation patterns significantly influence the distribution of functional mutations in cancer.