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Error-Prone DNA Repair Implicated in Analysis of Cancer Mutation Signature Clusters

NEW YORK (GenomeWeb) – A research duo has looked at tumor mutation clusters for clues to the mutagenic processes contributing to various cancer types.

"Clustered mutations are likely to be generated at the same moment in time, so by looking at several neighboring mutations at once, we can have a better understanding of what has damaged the DNA," first author Fran Supek, a group leader at Barcelona Institute of Science and Technology's Centre for Genomic Regulation (CRG), said in a statement. "[W]e show that focusing on patterns of clustered mutations and using a large number of cancer genomes, we can identify the culprits that cause mutations in tumors."

Supek and senior author Ben Lehner, a researcher affiliated with the CRG and Pompeu Fabra University, analyzed genome sequences for more than 1,000 tumors sequenced for the Cancer Genome Atlas and other efforts, searching for clustered mutations and mutation signatures that might point to mechanisms driving these genetic alterations. Their analysis led to nine clustered mutation signatures.

Along with mutation signatures associated with tobacco exposure or exposure to other known carcinogens, the team saw a signature that seemed to mark a switch from error-free mismatch DNA repair to an error-prone version of DNA repair, particularly around genes believed to be active based on their broader histone and chromatin context.

As they reported today in Cell, the researchers brought together somatic mutation profiles for more than 1,000 tumors that had been assessed by whole-genome sequencing, 733 of which were TCGA samples. Their analysis uncovered more than 92,600 single nucleotide mutation clusters in 1,159 tumors from a range of cancer types.

The nine resulting clustered mutation signatures included three smoking-related signatures, the team reported, as well as three signatures related to altered APOBEC cytosine deaminase activity.

In addition to analyses focused on mutation signature representation in kidney, bladder, brain, breast, and several other tumors types, the researchers delved more deeply into a mutation signature cluster related to hyper-mutation by a cytosine deaminase called AID, in combination with activity by a low fidelity and error-prone DNA polymerase encoded by the POLH gene. In a series of follow-up experiments, they saw evidence that exposure to carcinogens such as ultraviolet light or high alcohol levels may flip a switch between error-free and error-prone DNA repair at parts in the genome with H3K36me3 chromatin marks implicated in gene activity.

"Our results suggest that exposure to carcinogens, such as high amounts of alcohol, can shift the balance of the DNA repair machinery from a high-fidelity mode to an error-prone mode, causing the mutation rates to shoot up in the most important bits of the genome," Lehner said in a statement. "This error-prone repair generates a large number of mutations overall and is likely to be a major mutation source in human cells."

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