Loading...
Identification and validation of a previously missed mutational signature in colorectal cancer
Kazachkova, M. Otlu, B. Díaz-Gay, M. Abbasi, A. Moody, S. Perdomo, S. Wedge, D. C. Brennan, P. Stratton, M. R. Alexandrov, L. B.
Kazachkova, M.
Otlu, B.
Díaz-Gay, M.
Abbasi, A.
Moody, S.
Perdomo, S.
Wedge, D. C.
Brennan, P.
Stratton, M. R.
Alexandrov, L. B.
Abstract
Mutational signature analysis has greatly enhanced our understanding of the mutagenic processes found in cancer and normal tissues. As part of a recent study, we analyzed 802 treatment-naïve, microsatellite-stable colorectal cancers (CRC) and identified a de novo signature, SBS_D, which was conservatively decomposed into SBS18, a signature associated with reactive oxygen species. Here, we re-evaluate this decomposition and provide evidence that SBS_D represents a distinct mutational process from that of SBS18. Through an independent analysis of 2,616 whole-genome sequenced microsatellite-stable CRCs across three distinct cohorts, we demonstrate that SBS_D is consistently present at a similar prevalence, suggesting that this signature may have been previously overlooked. Using a naïve decomposition approach, we demonstrate that the pattern of SBS_D better aligns with signatures previously associated with deficiencies in DNA polymerase delta (POLD1) proofreading and mismatch repair. However, multiple lines of evidence, including the absence of pathogenic mutations in the exonuclease domain of POLD1 or in mismatch repair-associated genes, indicate that SBS_D is not driven by canonical defects in these DNA repair pathways. Overall, this study identifies a previously unrecognized mutational signature in microsatellite-stable CRC and proposes that its etiology may be linked to DNA repair infidelity emerging late in tumor development in samples without canonical defects in DNA repair pathways.
Description
Date
2025
Publisher
Collections
Files
Loading...
Found from Unpaywall
Adobe PDF, 22.83 MB
Keywords
Type
Preprint
Citation
Kazachkova M, Otlu B, Díaz-Gay M, Abbasi A, Moody S, Perdomo S, et al. Identification and Validation of a Previously Missed Mutational Signature in Colorectal Cancer. BioRxiv : the preprint server for biology. 2025 Jun 7. PubMed PMID: 40661437. Pubmed Central PMCID: PMC12258970 Therapeutics. L.B.A. is a co-founder, CSO, scientific advisory member, and consultant for io9 (now Acurion), has equity and receives income. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. L.B.A. is also a compensated member of the scientific advisory board of Inocras. L.B.A.’s spouse is an employee of Hologic, Inc. L.B.A. declares U.S. provisional applications filed with UCSD with serial numbers: 63/269,033; 63/289,601; 63/483,237; 63/412,835; and 63/492,348. L.B.A. and A.A. declare US provisional patent application filed with UCSD with serial number 63/366,392. L.B.A. is also an inventor of a US Patent 10,776,718 for source identification by non-negative matrix factorization. L.B.A., M.D.-G., M.R.S., P.B., S.P., and S.M. further declare a European patent application with application number EP25305077.7. All other authors declare that they have no competing interests. Epub 2025/07/15. eng.