Researchers Reveal Overlooked Colorectal Cancer DNA Repair Breakdown Fingerprint

Researchers from University of California San Diego and collaborators have identified a previously overlooked pattern of DNA mutations in colorectal cancer. Scientists use these patterns, known as mutational signatures, to investigate the biological and environmental processes that have damaged DNA during cancer development.

While the previously identified pattern had been detected in large cancer-genome datasets before, researchers had interpreted it as a combination of other, already known mutation patterns. When the researchers took a closer look, they found that the pattern was not associated with the known processes it had been attributed to. They also found the same pattern in three independent colorectal cancer datasets, together comprising 2,616 tumors, providing evidence that it is a genuine and recurring feature of some colorectal cancers.

The researchers found that the mutation pattern appears relatively late as colorectal tumors develop. This suggests that something may change during tumor development that causes cancer cells to accumulate a new type of DNA damage or copying error.

The researchers also found that tumors with the newly recognized pattern had more small insertions and deletions in their DNA. Because insertions and deletions can arise during DNA replication and repair, this finding provides an additional clue that the newly recognized pattern may be related to these processes.

More broadly, the study addresses one of the fundamental challenges in cancer genomics: Determining what unusual mutational patterns can reveal about the processes that shape cancer development. The work was completed by Team Mutographs, funded by Cancer Grand Challenges (CGC). Mutographs seeks to address the critical question about the relationship between mutational signatures and cancer development. This work now provides a foundation for Team CAUSE, a recently funded CGC team led by the study's senior author Ludmil Alexandrov, PhD, professor of cellular and molecular medicine and bioengineering at University of California San Diego and member of the Moores Cancer Center, which will build on these discoveries to identify the underlying mechanisms driving these and other unexplained mutational signatures in cancer.

The study ("Identification and validation of a previously missed mutational signature in colorectal cancer") was led by first author Mariya Kazachkova, PhD, and Alexandrov and published on Aug. 12, 2026, in Nature Communications.