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.

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Figure 1: Mutational signature analysis of 130 TCGA muscle-invasive urothelial tumors (TCGA-130 cohort).
Figure 2: Mutation enrichment analysis identifies an association between somatic ERCC2 mutations and activity of signature 5* in a discovery cohort, two validation cohorts, and the combined cohort.
Figure 3: Comparison of signature activities in tumors with wild-type versus mutant ERCC2 in the TCGA-130 cohort.
Figure 4: Overall mutation rates, mutational signature contributions, and mutational status of ERCC2 and other genes of interest in the combined cohort (TCGA-130 + DFCI/MSK-50 + BGI-99).
Figure 5: Effect of smoking and ERCC2 mutational status on signature 5* activity.
Figure 6: Association between clonality of ERCC2 mutations and clonality of signature 5* mutations.

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G.G. and J.K. were partially funded by the NIH TCGA Genome Data Analysis Center (U24CA143845). P.P. and A.K. were funded by the startup funds of G.G. at Massachusetts General Hospital. K.W.M. was partially funded by an American Society of Clinical Oncology (ASCO) Young Investigator Award and an American Society of Radiation Oncology (ASTRO) Junior Faculty Career Research Training Award. J.E.R. was partially funded by the Starr Cancer Consortium and the Memorial Sloan Kettering Geoffrey Beane Center. E.M.V.A. was partially funded by a Damon Runyon Clinical Investigator Award. A.D.D'A. was partially funded by the Starr Cancer Consortium. G.G. was partially funded by the Paul C. Zamecnik, MD, Chair in Oncology at Massachusetts General Hospital.

Author information

J.K. conceived the work, performed analyses, and wrote the manuscript. K.W.M. conceived the work, performed analyses, and wrote the manuscript. P.P. conceived the work, performed analyses, and wrote the manuscript. L.Z.B. performed analyses and edited the manuscript. A.K. performed analyses and edited the manuscript. G.T. performed analyses and edited the manuscript. D.J.K. contributed scientific insight and edited the manuscript. J.E.R. contributed scientific insight and edited the manuscript. E.M.V.A. conceived the work, contributed scientific insight, and edited the manuscript. A.D.D'A. conceived the work, contributed scientific insight, and edited the manuscript. G.G. conceived the work, oversaw the analyses, and wrote the manuscript.

Correspondence to Gad Getz.

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Competing interests

J.E.R. and E.M.V.A. have a patent pending for use of ERCC2 mutational status as a predictive biomarker for cisplatin sensitivity.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–18. (PDF 5465 kb)

Supplementary Table 1

Summary of the urothelial cancer cohorts. (XLSX 37 kb)

Supplementary Table 2

Numerical representation of signature 5* across cohorts. (XLSX 44 kb)

Supplementary Table 3

Summary of mutational signature contributions, ERCC2 mutational status, and smoking status for all cases. (XLSX 171 kb)

Supplementary Table 4

Comparison of mutational signatures in urothelial tumor cohorts to COSMIC mutational signatures. (XLSX 83 kb)

Supplementary Table 5

Comparison of signature 5* among urothelial tumor cohorts. (XLSX 50 kb)

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Kim, J., Mouw, K., Polak, P. et al. Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors. Nat Genet 48, 600–606 (2016).

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