Fig. 3: BRCA1/2 mutations in patients associate with increased tumor cell ADAR1 expression and activity.

A, B Pathological evaluation (A) and representative images (B) of ADAR1p150 cytoplasmic expression according to BRCA1 gene status (BRCA1-wildtype vs. BRCA1-mutant) in a cohort of 63 treatment-naïve triple-negative breast cancer (TNBC) patients. H-score of ADAR1p150 expression (range, 0–300). Violin plots indicate median, lower and upper quartiles; N = 32 [BRCA1-wildtype], N = 31 [BRCA1-mutant] values from individual tumor samples, two-tailed Mann-Whitney U test. P value, *=0.0359. Hematoxylin and eosin (H&E) and ADAR1p150 staining (magnification, ×20) are shown. Scale bars, 50 μm. C Percentage of TILs in TNBC tumors from the cohort described in A, according to cytoplasmic ADAR1p150 expression (based on A; ADAR1p150-low, lower quartile of H-score; ADAR1p150-high, upper quartile of H-score). Violin plots indicate median, lower and upper quartiles; N = 17 [BRCA1-wildtype], N = 15 [BRCA1-mutant] values from individual tumor samples, two-tailed Mann-Whitney U test. P value, **=0.0043. D, E Schematics illustrating the conceptual approach (D) and bioinformatic pipelines (E) used to evaluate A-to-I RNA editing levels from RNA-Seq data. F, G. A-to-I RNA editing levels displayed as RNA editing index (F) or number of RNA editing sites (G) in SUM149 BRCA1-Mut and BRCA1-Rev cells transfected with ADAR1 siRNA (P, Pool; #1). siCTRL, non-targeting, negative control siRNA. Bar plots indicate mean ± SD; n = 3 biological replicates, two-way ANOVA post hoc Tukey’s test. P values, ****< 0.0001. H Schematic of clinical history of the BRCA2-mutant and -revertant patient-derived xenografts (PDXs) MR-0009 and MR-0191; arrows indicate times of tumor biopsies for PDX establishment. Duration of each treatment delivered after diagnosis is indicated in months. Details of the corresponding BRCA2 mutations (germline vs. reversion) are presented to the left. I, J A-to-I RNA editing levels displayed as RNA editing index (I) or number of RNA editing sites (J) in BRCA2-mutant and -revertant PDXs MR-0009 and MR-0191. Bar plots indicate mean, where applicable; N = 1 [MR-0009 BRCA2-Mut], N = 2 [MR-0009 BRCA2-Rev], N = 1 [MR-0191 BRCA2-Mut], N = 1 [MR-0191 BRCA2-Rev] values from individual tumor samples. Source data are provided as a Source Data file. Elements of panel H were provided by Servier Medical Art (https://smart.servier.com/), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).