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Urothelial Tumor Sequences Reveal Mutational Signature Associated with DNA Repair

NEW YORK (GenomeWeb) – A team reporting in Nature Genetics today has characterized the mutational signature that marks tumors that contain somatic mutations affecting the nucleotide excision repair system, a DNA repair pathway.

Researchers from the Broad Institute, Harvard Medical School, Massachusetts General Hospital, and elsewhere used an existing mutation signature analysis approach to profile 130 muscle-invasive urothelial cancer samples from the Cancer Genome Atlas project. Urothelial cancers tend to have higher-than-usual rates of mutation to the DNA helicase enzyme-coding gene ERCC2, they explained. And that helicase has a key role in the NER process, unraveling the strands of DNA that neighbor a break in need of repair.

Defects in NER-based DNA repair appears to prompt diverse base changes in the resulting tumors, leading to more so-called signature 5* mutations than usual. The team also saw an uptick in this mutational signature in past smokers, suggesting tobacco smoke-related DNA damage may boost urothelial cancer risk in the presence of diminished DNA repair capabilities.

"Together, these findings identify the first NER-related mutational signature, to our knowledge, and underscore the importance of both exposure to DNA-damaging agents and operation of DNA repair pathways in the activities of mutational signatures," senior author Gad Getz, director of the Broad Institute's cancer genome computational analysis group, and his co-authors wrote.

When they analyzed mutational signatures in 130 urothelial tumors from TCGA, Getz and his colleagues uncovered known mutational signatures related to APOBEC-mediated mutagenesis and age-related mutagenesis. But they also detected an unreported mutational signature marked by broad base changes that shared some features with mutation signature 5 in the COSMIC database.

A closer look at this signature suggested it mainly occurred in a set of 16 urothelial tumors with non-silent, somatic ERCC2 gene mutations — a pattern the team verified through analyses of data for 149 more muscle-invasive urothelial tumors from two cohorts.

In the first follow-up set of 50 urothelial tumors, the researchers identified some 220 signature 5* mutations in nine tumors with ERCC2 mutations, compared with just 32 such mutations in the remaining, ERCC2 mutation-free samples. Similarly, they saw a jump in signature 5* mutations in tumors with non-silent ERCC2 mutations from another set of 99 muscle-invasive or non-invasive urothelial tumors.

Although the team saw signature 5* mutations in tumors with or without somatic mutations to ERCC2, the signature was far more common in tumors with non-silent, missense mutations to ERCC2, particularly in the muscle-invasive urothelial tumors.

The researchers saw a small jump in signature 5* activity in tumors from individuals with a history of smoking, consistent with the notion that DNA repair is especially important for those exposed to DNA-damaging agents.

"Together, our data suggest that the genomic imprint of signature 5* depends on both the extent of DNA damage (from tobacco or other mutagens) and the relative activity of high- and low-fidelity DNA repair pathways, which is altered in the setting of an ERCC2 mutation," Getz and co-authors wrote. 

"Further studies will be needed to characterize the mechanisms underlying signature 5* activity in tumors that lack an ERCC2 mutation and to explore potential relationships between signature 5* activity and clinically relevant endpoints such as treatment response," they concluded.