Error-Prone DNA Repair Targets the H3K36me3 Chromatin of Active Genes

Characterization of passenger somatic mutations has identified different mutation signatures associated with specific nucleotide changes and provided insight into mutational processes in a cancer cell; for instance, C>T and C>G mutations in the TpCp(A/T)p context are associated with members of the APOBEC3 family of cytosine deaminases. To identify additional processes driving mutation in cancer, Supek and Lehner characterized the landscape of clustered mutations in 1,159 human tumor genomes. Nine clustered mutation signatures were associated with the majority of frequent mutations compared to unclustered mutation signatures, and three of the clustered mutation signatures were associated with APOBEC3A and APOBEC3B enzymes. The clustered mutation signature C4, which was characterized by changes at A:T nucleotide pairs, exhibited the highest mutation burden and specificity for cancers of lymphoid origin, suggesting a link to somatic hypermutation, which is initiated by the cytosine deaminase AID, and the error-prone DNA polymerase eta (POLH, encoded by POLH), which preferentially causes A>G changes during replication of undamaged DNA. POLH-associated signature mutations were directed toward the 5′ end of AID-associated genes in lymphoid tumors and the 3′ end of active genes in solid tumors and were associated with H3K4me3 and H3K27ac marks in lymphoid tumors and the H3K36me3 mark in solid tumors. Further, canonical and error-prone noncanonical mismatch repair activity was shown to be critical for POLH-associated clustered mutations at H3K36me3 marks in active genes, and error-prone repair also contributed to the generation of unclustered mutations. POLH-spectrum mutagenesis correlated with the ultraviolet light mutation signature and was associated with driver mutations in melanoma. Similarly, alcohol was associated with POLH-spectrum burden in multiple cancer types previously linked to alcohol consumption, and tobacco smoking was associated with POLH-spectrum burden in urinary tract tumors and signature C5 burden in different cancer types in ever-smoker patients. These results identify clustered mutation signatures in cancer and provide further insights into cancer etiology, prevention, and therapy.

Supek F, Lehner B. Clustered mutation signatures reveal that error-prone DNA repair targets mutations to active genes. Cell 2017;170:P534–47.e23.

• ©2017 American Association for Cancer Research.