Kim, JaegilMouw, KentPolak, PazBraunstein, Lior ZKamburov, AtanasKwiatkowski, DavidRosenberg, Jonathan EVan Allen, EliezerD'Andrea, AlanGetz, Gad2016-11-182016Kim, Jaegil, Kent W Mouw, Paz Polak, Lior Z Braunstein, Atanas Kamburov, David J Kwiatkowski, Jonathan E Rosenberg, Eliezer M Van Allen, Alan D'Andrea, and Gad Getz. 2016. “Somatic ERCC2 Mutations Are Associated with a Distinct Genomic Signature in Urothelial Tumors.” Nature genetics 48 (6): 600-606. doi:10.1038/ng.3557. http://dx.doi.org/10.1038/ng.3557.1061-4036http://nrs.harvard.edu/urn-3:HUL.InstRepos:29408437Alterations in DNA repair pathways are common in tumors and can result in characteristic mutational signatures; however, a specific mutational signature associated with somatic alterations in the nucleotide excision repair (NER) pathway has not yet been identified. Here, we examine the mutational processes operating in urothelial cancer, a tumor type in which the core NER gene ERCC2 is significantly mutated. Analysis of three independent urothelial tumor cohorts reveals a strong association between somatic ERCC2 mutations and activity of a mutational signature characterized by a broad spectrum of base changes. In addition, we note an association between activity of this signature and smoking that is independent of ERCC2 mutation status, providing genomic evidence of tobacco-related mutagenesis in urothelial cancer. Together, these analyses identify the first NER-related mutational signature and highlight the related roles of DNA damage and subsequent DNA repair in shaping the tumor mutational landscape.en-USJournal Article2016-11-1810.1038/ng.3557