Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors.
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.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jaegil
J
Kim
Department of Radiation Oncology, Brigham & Women's Hospital, Dana-Farber Cancer Institute, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
Kent W
KW
Mouw
Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Harvard Medical School, Boston, MA, USA.|Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.|Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
Paz
P
Polak
Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Harvard Medical School, Boston, MA, USA.
Lior Z
LZ
Braunstein
Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Harvard Medical School, Boston, MA, USA.|Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.|Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
Atanas
A
Kamburov
Harvard Medical School, Boston, MA, USA.|Division of Pulmonary Medicine, Brigham & Women's Hospital, Boston, MA, USA.
David J
DJ
Kwiatkowski
Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Jonathan E
JE
Rosenberg
Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Harvard Medical School, Boston, MA, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Eliezer M
EM
Van Allen
Department of Radiation Oncology, Brigham & Women's Hospital, Dana-Farber Cancer Institute, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.|Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA, USA.
Alan
A
D'Andrea
Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Harvard Medical School, Boston, MA, USA.|Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.|Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
Gad
G
Getz
D015331:Cohort Studies; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D009154:Mutation; D001749:Urinary Bladder Neoplasms / Q000209:etiology / Q000235:genetics*; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*; D014026:Nicotiana
D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human