Mutational signature SBS8 predominantly arises due to late replication errors in cancer

Area of Science:

• Genomics
• Cancer Biology
• Epigenetics

Background:

• Somatic mutations in cancer, while often passengers, offer insights into mutagenesis and DNA repair.
• Mutational signature SBS8 is prevalent across many cancers, yet its origin remains unclear.
• Understanding mutational signatures is crucial for deciphering cancer development and therapeutic strategies.

Purpose of the Study:

• To investigate the etiology of mutational signature SBS8 by integrating genomic, epigenomic, and cellular data.
• To identify the specific genomic and epigenomic contexts associated with SBS8 occurrence.
• To elucidate the relationship between SBS8, replication timing, and DNA repair defects in cancer progression.

Main Methods:

• Development of genome-wide composite epigenomic context-maps incorporating genomic, epigenomic, and cellular process features.
• Analysis of somatic mutation data from diverse cancer types within their established epigenomic contexts.
• Correlation analysis of SBS8 frequency with replication timing, replication speed, and checkpoint function.

Main Results:

• SBS8 signature preferentially localizes to gene-poor, lamina-proximal, late-replicating heterochromatin domains.
• The proportion of SBS8 mutations increases with replication timing and speed in tumor genomes.
• Checkpoint defects were observed to further promote the SBS8 signature, indicating a role in cancer progression.

Conclusions:

• SBS8 likely originates from uncorrected errors during late DNA replication in the context of cancer progression.
• These findings reconcile differing viewpoints on the etiology of SBS8 and its association with other mutational signatures.
• The study provides a mechanistic understanding of SBS8, linking it to specific epigenomic features and cellular processes.