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Nat Genet. 2016 Jun;48(6):600-606. doi: 10.1038/ng.3557. Epub 2016 Apr 25.

Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors.

Kim J#1, Mouw KW#2,3, Polak P#1,3,4,5, Braunstein LZ1,3, Kamburov A1,3,4,5, Kwiatkowski DJ3,6, Rosenberg JE7, Van Allen EM1,3,8, D'Andrea A2,3,9, Getz G1,3,4,5.

Author information

1
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
2
Department of Radiation Oncology, Brigham & Women's Hospital, Dana-Farber Cancer Institute, Boston, MA, USA.
3
Harvard Medical School, Boston, MA, USA.
4
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
5
Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
6
Division of Pulmonary Medicine, Brigham & Women's Hospital, Boston, MA, USA.
7
Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
8
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
9
Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA, USA.
#
Contributed equally

Abstract

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.

PMID:
27111033
PMCID:
PMC4936490
DOI:
10.1038/ng.3557
[Indexed for MEDLINE]
Free PMC Article

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