Figure 2. Telomere-binding protein dependencies are associated with telomere content and TP53 mutation status.

(a) Pairwise plot of Pearson correlations between dependencies of all genes in the Avana dataset and CCLE WGS telomere content (x-axis, n = 210–211 cell lines) and GDSC WES telomere content (y-axis, n = 420–426 cell lines) estimates. (b) Pairwise plot of significance levels of correlations shown in (a) with correction for multiple hypothesis testing. (c) Pairwise Pearson correlation matrix between Avana dependencies among CST members and five shelterin components (n = 796–808 cell lines; Supplementary file 3). (d) Associations of CST and shelterin member Avana dependency scores with damaging and hotspot mutations (n = 796–808 cell lines). For each gene dependency, mutation associations were computed using rank-biserial correlations with mutants and wild-types as the two categories. p Values determined using two-sided Mann-Whitney U test. (e) Associations of shelterin member DRIVE dependency scores with damaging and hotspot mutations (n = 372–375 cell lines; Supplementary file 3) under the same scheme used in (d). (f) Network schematic of the co-dependency matrix shown in (c) and annotated with association with telomere content or TP53 mutation status.

Figure 2—figure supplement 1. Telomere content and telomere protein dependencies.

(a) Scatterplots of z-scored log₂-transformed telomere content estimates from the CCLE WGS (left) and GDSC WES (center) datasets against sensitivity to members of the CST complex measured in the Avana dataset. Also shown are comparisons with raw telomere content from CCLE WGS samples (right). (b) Distribution of Pearson correlations between telomere content estimates from CCLE WGS and GDSC WES datasets and all gene dependencies in the Avana CRISPR-Cas9 dataset (vs. CCLE WGS: n = 192–210 cell lines, vs. GDSC WES: n = 395–416 cell lines; Supplementary file 3). (c) Selected correlations between CCLE WGS and GDSC WES-derived telomere content and Avana dependencies of CST and shelterin complex members.

Figure 2—figure supplement 2. TP53 mutation status and shelterin member dependencies.

(a) Codependencies of CST and shelterin complex members in the Avana CRISPR-Cas9 dataset as measured by Pearson correlation and the associated two-sided P value (n = 793–808 cell lines). q-values are shown for correlations between each gene indicated on the x-axis and all other genes, with q-values transformed and ranked by the sign of the correlation. (b) Repeat of codependency analysis in (a), but for DRIVE RNAi dependencies (n = 88–386 cell lines). (c and d) comparison of dependencies of select members (Avana and DRIVE, respectively) with respect to TP53 hotspot mutation status. Boxes, interquartile range (IQR); center lines, median; whiskers, maximum, and minimum or 1.5 × IQR; notches, 95% confidence interval of bootstrapped median using 1000 samples and a Gaussian-based asymptotic approximation. p Values determined by two-sided Mann-Whitney U test.