Researchers at the University of California San Diego and collaborating institutions have identified and validated a previously overlooked pattern of DNA mutations in colorectal cancer, revealing a recurring genomic feature that may reflect changes in the way tumor cells replicate or repair their DNA. The finding adds a new piece to the complex molecular history recorded in cancer genomes and could help scientists understand how colorectal tumors evolve over time. The study, published in Nature Communications, suggests that the signature emerges relatively late during tumor development and is associated with an increased number of small insertions and deletions, or indels, in tumor DNA.
Cancer genomes are not shaped by random damage alone. As tumors develop, their cells accumulate characteristic combinations of mutations that can arise from chemical exposure, ultraviolet radiation, defects in DNA repair, errors during DNA replication, or other biological processes. These combinations are called mutational signatures. By studying them, researchers attempt to reconstruct the mechanisms that have damaged a tumor’s DNA and determine when those mechanisms may have become active. Mutational signatures are typically identified by analyzing the types of DNA changes found across large collections of tumor genomes, including the specific DNA bases altered and the sequence contexts in which those changes occur.
The newly recognized colorectal cancer signature had appeared in earlier analyses of large cancer-genome datasets, but it was not initially considered a distinct biological pattern. Instead, researchers interpreted it as a mixture of other mutational signatures that had already been described. This type of misclassification can occur when a mutation pattern is relatively weak, overlaps with the features of known signatures, or appears in only a subset of tumors. Statistical models may then assign the mutations to several established processes rather than recognizing that they originate from a separate and recurring source.
Mariya Kazachkova, PhD, the study’s first author, Ludmil Alexandrov, PhD, the senior author, and their colleagues revisited the pattern using a more detailed analysis of colorectal cancer genomes. Their investigation showed that the mutations did not display the expected relationship to the biological processes associated with the signatures to which they had previously been attributed. Instead, the pattern had its own distribution of base substitutions and sequence contexts, indicating that it should be treated as an independent mutational signature rather than as a composite of other known processes.
The researchers then tested whether the pattern could be reproduced in separate collections of colorectal tumors. It was detected in three independent datasets that together included 2,616 tumors. Its repeated appearance across unrelated cohorts provided evidence that the signature is not an artifact of a particular sequencing project, statistical method, or patient group. Validation in independent datasets is a crucial step in mutational-signature research because it demonstrates that a pattern is biologically recurring and not simply the result of technical noise, sampling bias, or an unusual feature of one cancer collection.
The timing of the signature within tumor evolution offered another important clue. According to the researchers, the pattern appears relatively late as colorectal tumors develop. This suggests that the cells may undergo a transition during tumor progression that changes their exposure to DNA damage or disrupts the systems responsible for copying and repairing genetic material. A late-emerging signature could reflect the loss of a repair function, a change in replication stress, alterations in cell-cycle control, or the development of a new tumor microenvironment. The current study does not establish which of these mechanisms is responsible, but it narrows the search by linking the signature to a particular stage of cancer evolution.
Tumors carrying the signature also contained more small insertions and deletions than tumors without it. Indels are mutations in which one or more DNA bases are added or removed from the genome. They can occur when DNA polymerases, the enzymes that copy DNA, lose track of repetitive sequences or when damaged DNA is processed incorrectly. Indels may also arise when repair pathways join broken or mismatched DNA ends. Their increased frequency in tumors with the newly recognized signature supports the possibility that the pattern is connected to replication or repair abnormalities rather than being caused solely by an external mutagen.
The relationship between single-base substitutions and indels is especially significant because the two mutation classes can preserve different clues about the underlying biological process. A base substitution may indicate that one nucleotide was chemically altered or miscopied, while an indel may point to slippage during replication, faulty gap filling, or inaccurate repair of a DNA lesion. When both types of mutations increase together, researchers can begin to construct a more complete model of the cellular malfunction involved. However, the presence of indels alone does not identify a specific pathway, and additional laboratory experiments will be required to determine whether the signature is caused by a known repair defect, an as-yet-unrecognized mechanism, or several interacting processes.
The discovery also highlights a broader challenge in cancer genomics: mutational signatures are mathematical patterns, but their biological explanations must be tested experimentally. A signature can show that a particular form of DNA damage has occurred without revealing exactly what caused it. Two different molecular processes may produce similar mutation profiles, while one process may generate different profiles depending on the cell type, DNA-repair environment, or stage of tumor development. The researchers therefore view the newly identified signature as a starting point for investigating the mechanism behind it, rather than as a complete explanation of colorectal cancer progression.
The work was completed by Team Mutographs, an international research effort funded through Cancer Grand Challenges, which seeks to clarify how mutational signatures relate to the causes and development of cancer. The findings now provide a foundation for Team CAUSE, a newly funded Cancer Grand Challenges team led by Alexandrov. Team CAUSE will build on this research to investigate the mechanisms driving unexplained mutational signatures across cancer types. By combining tumor sequencing with experimental models and studies of DNA replication and repair, the team aims to connect distinctive genomic patterns with the cellular events that produce them. Such connections could eventually improve the classification of tumors, reveal weaknesses that can be targeted therapeutically, and help researchers distinguish the biological histories of cancers that appear similar under the microscope.
The study, titled “Identification and validation of a previously missed mutational signature in colorectal cancer,” was led by Kazachkova and Alexandrov and published on August 12, 2026, in Nature Communications. Its central message is that cancer genomes may still contain important patterns hidden in plain sight. As analytical methods become more sensitive and researchers compare findings across larger and more diverse tumor collections, signatures previously dismissed as mixtures may be recognized as distinct records of tumor evolution. In colorectal cancer, the newly validated pattern points toward a late-stage change involving DNA replication or repair and offers scientists a new route for investigating how malignant cells acquire the mutations that enable them to survive and expand.
Subject of Research: Colorectal cancer mutational signatures and the DNA replication or repair processes associated with tumor evolution.
Article Title: Identification and validation of a previously missed mutational signature in colorectal cancer
News Publication Date: August 12, 2026
Web References: https://www.nature.com/articles/s41467-026-76472-w
References: Nature Communications study led by Mariya Kazachkova, PhD, and Ludmil Alexandrov, PhD.
Keywords: Colorectal cancer, cancer genomics, mutational signatures, DNA mutations, DNA replication, DNA repair, insertions and deletions, indels, tumor evolution, Cancer Grand Challenges, Team Mutographs, Team CAUSE
