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

Jaegil Kim1, Kent W Mouw2,3, Paz Polak1,3,4,5

  • 1Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Nature Genetics
|April 26, 2016
PubMed

Insights

Researchers identified a new mutational signature linked to DNA repair in urothelial cancer. This signature is associated with ERCC2 gene mutations and smoking, offering insights into tumor development.

Area of Science:

  • Genomic instability and cancer biology.
  • DNA repair mechanisms and mutagenesis.
  • Urothelial carcinoma and cancer genomics.

Background:

  • Somatic alterations in DNA repair pathways are frequent in tumors, often yielding distinct mutational signatures.
  • A specific mutational signature linked to nucleotide-excision repair (NER) pathway alterations has not been previously identified.
  • The ERCC2 gene, crucial for NER, is frequently mutated in urothelial cancer.

Purpose of the Study:

  • To investigate the mutational processes in urothelial cancer.
  • To identify a specific mutational signature associated with somatic alterations in the NER pathway.
  • To explore the relationship between this signature, ERCC2 mutations, and smoking in urothelial cancer.

Main Methods:

  • Analysis of three independent urothelial tumor cohorts.
  • Examination of mutational signatures associated with somatic ERCC2 mutations.
  • Assessment of the association between the identified signature, ERCC2 status, and smoking.

Main Results:

  • A strong association was found between somatic ERCC2 mutations and a mutational signature with a broad spectrum of base changes.
  • This signature's activity was also linked to smoking, independent of ERCC2 mutation status.
  • Genomic evidence supports tobacco-related mutagenesis in urothelial cancer.

Conclusions:

  • An NER-related mutational signature has been identified in urothelial cancer.
  • This signature is associated with both ERCC2 mutations and smoking.
  • The findings highlight the interconnected roles of DNA damage and repair in shaping the tumor mutational landscape.

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