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

. 2016 Jun;48(6):600-606.

doi: 10.1038/ng.3557. Epub 2016 Apr 25.

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

Jaegil Kim et al. Nat Genet. 2016 Jun.

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.

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Figures

Figure 1
Figure 1

Mutational signature analysis of 130 TCGA muscle-invasive urothelial tumors (TCGA-130 cohort). (a) The spectrum of base changes identified in the TCGA-130 cohort displayed as the mutated pyrimidine and the adjacent 3' and 5' bases. (b) A Bayesian non-negative matrix factorization algorithm was applied to identify signatures from the matrix of mutation counts across tumors. Four distinct mutational signatures were identified.

Figure 2
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. For genes mutated in >5% of samples in each cohort, the number of mutations attributed to signature 5* was compared in tumors with a wild-type versus mutated copy of the gene while controlling for overall mutation burden per gene and sample. Genes with FDR Q<0.1 are highlighted in red. ERCC2 was the only gene that was significant in each of the cohorts. COMB-279 refers to the combined cohort (TCGA-130 + DFCI/MSK-50 + BGI-99).

Figure 3
Figure 3

Comparison of signature activities in wild-type (WT) versus mutant ERCC2 tumors in the TCGA-130 cohort. (a) The estimated number of signature 5* mutations was significantly higher in ERCC2 mutated tumors compared to WT ERCC2 tumors. (b) Estimated number of mutations attributed to the other three mutational signatures identified in the TCGA-130 cohort. The median estimated number of mutations is shown in parentheses, and p-values were computed using a one-tailed permutation test.

Figure 4
Figure 4

Overall mutation rate, mutational signature contributions, and mutational status of ERCC2 and other genes of interest in the combined cohort (TCGA-130 + DFCI/MSK-50 + BGI-99). Each column represents a tumor. Overall mutation burden is shown at the top, followed by the estimated contribution of each of the four mutational signatures to the overall mutation burden (samples arranged in descending order of signature 5* activity), cohort, smoking status, and stage (muscle invasive versus non-muscle invasive). In the bottom half of the figure, the mutational status of ERCC2 and other genes of interest are color-coded by type of mutation. Somatic events in non-ERCC2 NER pathway genes are collapsed in a single track (see Supplementary Figure 10 for expanded NER pathway gene list) and are followed by other significantly mutated genes in urothelial cancer (TP53, RB1, etc).

Figure 5
Figure 5

Effect of smoking and ERCC2 mutational status on signature 5* activity. (a) There was no significant difference in the total number of mutations (SNVs) in smokers compared to non-smokers in the combined TCGA-130 + DFCI/MSK-50 cohort. The median number of mutations is shown in parentheses and p-values were calculated using the Wilcoxon rank-sum test. (b) The estimated number of signature 5* mutations was significantly higher in smokers than in non-smokers. (c) Among patients with wild-type (WT) ERCC2 tumors, the number of signature 5* mutations was significantly higher in smokers than non-smokers, whereas smoking was not associated with a further increase in signature 5* activity among patients with ERCC2 mutated tumors. The association between smoking and signature 5* activity is not as strong as the association between ERCC2 and signature 5*.

Figure 6
Figure 6

Association between clonality of ERCC2 mutations and clonality of signature 5* mutations. For tumors with a clonal ERCC2 mutation (defined as probability[cancer cell fraction≥0.95]>0.5); red circles, left panel), the majority of signature 5* mutations were clonal (clonal:subclonal ratio~5). For tumors with a subclonal ERCC2 mutation (blue circles, center panel) or WT ERCC2 (green circles, right panel), the ratio of clonal to subclonal signature 5* mutations was much lower (clonal:subclonal ratio~1.1 and ~1.9, respectively).

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