Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors
A partir de 3 bases de données indépendantes portant sur des échantillons tumoraux prélevés sur des patients atteints d'une tumeur urothéliale, cette étude identifie une association entre des mutations somatiques du gène ERCC2, un gène du système de réparation par excision de nucléotides, et une signature mutationnelle dont l'activité est reliée au tabagisme
Alterations 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 demonstrates a strong association between somatic ERCC2 mutations and the activity of a mutational signature characterized by a broad spectrum of base changes. In addition, we note an association between the 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 an NER-related mutational signature and highlight the related roles of DNA damage and subsequent DNA repair in shaping tumor mutational landscape.
Nature Genetics 2016