Fig. 3: Synthetic lethal effects associated with HR deficiency and their validation in isogenic screens.
From: The transcriptomic architecture of common cancers reflects synthetic lethal interactions
a, Box plots illustrating hyperexpressed genes (effect size >0) in different subgroups of patients with HRD. The dots indicate genes in corresponding SLMs (hyperexpression effect size ≥0.25 and FDR-adjusted P < 0.05, and synthetic lethal effect size ≤−0.25 and P < 0.01; P values calculated using unpaired, two-sided, moderated Student’s t-test) across SCAN-B TNBC, TCGA breast (BRCA) TNBC, TCGA prostate (PRAD) and TCGA ovarian (OV) cancer datasets. Example BRCA1/2 synthetic lethal effects are highlighted. The number of genes in SLMs and P value of significance for overlap between synthetic lethal and hyperexpressed genes are shown. Box plots show the first quartile, median and third quartile, with whiskers extended to points closest to Q1 − 1.5× the IQR and Q3 + 1.5× the IQR. b, Scatter plot illustrating BRCA1 synthetic lethal effects identified via isogenic SUM149 screen. Delta (Δ) represents the difference in viability (normalized z-score) between SUM149Mutant and SUM149Revertant cells. Key BRCA1/2 synthetic lethal genes are highlighted. c, Scatter plot illustrating BRCA2 synthetic lethal effects identified in isogenic Capan1 screen (details as in b). d,e, Scatter plots illustrating BRCA1 and BRCA2 synthetic lethal effects identified in two previously published7 BRCA1/2 isogenic screens in RPE1 (d) and DLD1 (e) cells. For visualization purposes, published CRISPRCount Analysis (CCA) scores had the penalty constant (10,000) added back to negative scores <−9,000 and the resulting CCA scores were transformed to z-scores and multiplied by −1. Key synthetic lethal genes are highlighted. f, Top, Venn diagram showing the overlap between DepMap-identified BRCA1/2 synthetic lethal genes and BRCA1/2 synthetic lethal genes identified in both in-house (either SUM149 or Capan1) and published (either RPE1 or DLD1) isogenic CRISPR–Cas9 screens. Bottom, Venn diagrams showing the overlap between BRCA1/2 synthetic lethal genes found in both DepMap and BRCA1/2 isogenic screens (18 genes) and hyperexpressed genes in HRD+ cancers from SCAN-B and TCGA TNBC datasets. Over-representation P values are reported for all Venn diagrams (Fisher’s exact test).
