Identification and Validation of a Previously Missed Mutational Signature in Colorectal Cancer

Area of Science:

• Genomics
• Cancer Research
• Molecular Biology

Background:

• Mutational signature analysis reveals mutagenic processes in cancer.
• A previous study identified a novel signature (SBS_D) in microsatellite-stable colorectal cancer (CRC), initially decomposed into SBS18.
• SBS18 is associated with reactive oxygen species.

Purpose of the Study:

• To re-evaluate the decomposition of SBS_D and confirm its distinction from SBS18.
• To investigate the prevalence and potential etiology of SBS_D in CRC.
• To determine if SBS_D is linked to known DNA repair deficiencies.

Main Methods:

• Analysis of 802 treatment-naïve, microsatellite-stable CRC genomes.
• Independent analysis of 2,616 whole-genome sequenced microsatellite-stable CRCs across three cohorts.
• Naïve decomposition approach to compare SBS_D with known signatures.

Main Results:

• SBS_D was confirmed as a distinct mutational process, separate from SBS18.
• SBS_D showed consistent prevalence across independent CRC cohorts, suggesting it was previously overlooked.
• SBS_D pattern aligned with signatures linked to DNA polymerase delta (POLD1) proofreading and mismatch repair deficiencies.
• Absence of pathogenic mutations in POLD1 or mismatch repair genes ruled out canonical defects as the cause of SBS_D.

Conclusions:

• A previously unrecognized mutational signature, SBS_D, was identified in microsatellite-stable CRC.
• SBS_D is not driven by canonical defects in POLD1 proofreading or mismatch repair pathways.
• The etiology of SBS_D may involve DNA repair infidelity occurring late in tumor development without detectable genetic defects in repair pathways.