Identification and validation of a previously missed mutational signature in colorectal cancer

Date

2026-12-01

Author

Kazachkova, Mariya
Otlu Sarıtaş, Burçak
Díaz-Gay, Marcos
Abbasi, Ammal
Moody, Sarah
Jiang, Zichen
Perdomo, Sandra
Wedge, David. C.
Brennan, Paul
Stratton, Michael. R.
Alexandrov, Ludmil. B.

Metadata

Show full item record

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Item Usage Stats

535
views

0
downloads

Cite This

Mutational signature analysis has enhanced our understanding of mutagenic processes. In a recent study, we analyzed 802 microsatellite-stable colorectal cancers (CRC) and identified a de novo signature, SBS_D, which was decomposed into SBS18. Here, we re-evaluate this decomposition and provide evidence that SBS_D represents a distinct mutational process from SBS18. Through an analysis of 2,616 CRCs across three independent cohorts, we demonstrate that SBS_D is consistently present, suggesting this signature may have been previously overlooked. We illustrate that the pattern of SBS_D better aligns with signatures associated with deficiencies in DNA repair, despite evidence that SBS_D is not driven by canonical defects in these DNA repair pathways. Overall, this study identifies a previously unrecognized mutational signature in DNA repair-proficient CRC and proposes that its etiology may be linked to DNA repair infidelity emerging late in tumor development. SBS_D has been submitted to the COSMIC database and provisionally designated as SBS111.

URI

https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=105050143985&origin=inward
https://hdl.handle.net/11511/120918

Collections

Graduate School of Informatics, Article