ERCC2 Mutations Are Associated with a Specific Mutational Signature

DNA repair pathway mutations occur frequently in tumors, and mutational signatures associated with defective DNA repair have been identified, including those associated with deficient homologous recombination or mismatch repair. The nucleotide-excision repair (NER) pathway gene ERCC2 is mutated in 6% to 18% of urothelial tumors; however, mutational signatures associated with abnormal NER have yet to be described. Kim, Mouw, Polak, and colleagues performed mutational signature analysis on 130 urothelial tumors from The Cancer Genome Atlas and identified 4 independent mutational signatures that matched those found in other tumor types previously described in the Catalogue of Somatic Mutations in Cancer (COSMIC). Two of the signatures have been ascribed to APOBEC-mediated mutagenesis, the third is associated with C>T transitions at CpG dinucleotides and presumed to be due to 5-methylcytosine deamination, and the fourth was similar to COSMIC signature 5, a signature with a broad spectrum of base changes and an unknown etiology. This signature, denoted signature 5*, was significantly enriched in tumors with ERCC2 mutations, an association that was validated in two independent urothelial tumor cohorts. Several tumors without ERCC2 mutations that still exhibited high signature 5* activity harbored a somatic or germline mutation in a different NER pathway gene, providing further evidence for the role of defective NER in this mutational signature and suggesting that defects in NER may contribute to signature 5* mutations. Further, smoking, which is a risk factor for urothelial cancer, was also linked to increased signature 5* activity, identifying a tobacco-associated signature in urothelial cancer. ERCC2 mutations are enriched in urothelial tumors that respond to platinum-based chemotherapy, and patients who responded to cisplatin exhibited higher signature 5* activity than nonresponders. Taken together, these findings provide insight into the development of urothelial tumors and link the mutational signature 5* and related COSMIC signature 5 with NER.

Kim J, Mouw KW, Polak P, Braunstein LZ, Kamburov A, Tiao G, et al. Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors. Nat Genet 2016 April 25 [Epub ahead of print].