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. 2022 Nov 21;11:e82860. doi: 10.7554/eLife.82860

Figure 1. ATAD1 is co-deleted with PTEN in cancer and its loss confers synthetic lethal vulnerabilities.

(A) Schematic of PTEN and ATAD1 loci. (B) Oncoprint plots from three TCGA studies of cancer. ATAD1 and PTEN alteration frequencies are shown, with blue bars indicating deep deletions. (C) Frequency of ATAD1 deep deletions across various cancer types; data from cBioPortal. (D) CRISPR screen design for wild-type (WT) and ATAD1∆ Jurkat cells. (E) Jurkat CRISPR screen results; each point represents one gene. CRISPR score (CS) values were calculated by taking the average log2 fold-change in relative abundance of all sgRNAs targeting a given gene over 14 population doublings. WT CS values are shown on the y-axis. The CS values per gene for each of the two ATAD1∆ clones were averaged and are plotted on the x-axis. The top 10 genes that were differentially essential between WT and ATAD1∆ are labeled in blue, with MARCH5 labeled in red. (F) CRISPR screen design for HGC27 cells (Chr10q23 deletion, ATAD1-null) comparing gene essentiality in ATAD1 complemented cells or empty vector (EV) (ATAD1-null) control. (G) HGC27 CRISPR screen results; CS values are as described for (E). The x-axis depicts CS for the ATAD1-null condition of EV-transduced cells, and the y-axis depicts CS for the ATAD1-complemented (+ATAD1) condition. Labels are as described for (E).

Figure 1—source data 1. Source data used to make Figure 1.

Figure 1.

Figure 1—figure supplement 1. ATAD1 is co-deleted with PTEN as a passenger.

Figure 1—figure supplement 1.

(A) Summary of IHC study on PTEN-null prostate adenocarcinoma (PrAd). (B) Representative histology of tumor samples from patients with PTEN-null tumors. (C) Representative histology of PTEN-positive tumors. (D) Somatic mutations in the PTEN (D) or ATAD1 (E) loci, from TCGA Pan-Cancer Atlas studies (32 studies; n=10,528 samples); note logarithmic scale on y-axis.
Figure 1—figure supplement 1—source data 1. Source data used to make Figure 1—figure supplement 1.
Figure 1—figure supplement 2. Characterization of co-deleted genes on Chr10q23.

Figure 1—figure supplement 2.

(A) Schematic of human chr10, with the 10q23 region highlighted with a red box, and CNV of 698 tumors from patients with metastatic castrate-resistant prostate cancer. Blue horizontal bars indicate deletion of the corresponding region of the chromosome, with darker blue indicating deeper deletion (i.e. lower copy number). Red indicates amplification. (B) Plot of deep deletion frequency vs. chromosomal location. Each point corresponds to the genomic coordinates of the start codon for the corresponding gene, as annotated in cBioPortal, and the frequency of deep deletions in the cohort shown in (A). The x-axis is to scale, but only approximately to scale in relation to (A).
Figure 1—figure supplement 3. Supporting data for Jurkat CRISPR screens.

Figure 1—figure supplement 3.

(A) Western blot demonstrating PTEN and ATAD1 status across cell lines. (B) Western blot verification of ATAD1 deficiency of ATAD1∆ cell lines. (C) Proliferation of wild-type (WT) and ATAD1∆ cell lines over 4 days; mean ± SD for n=3 independent experiments. (D) Differential CRISPR scores for the two ATAD1∆ clonal cell lines relative to WT; Pearson coefficient = 0.51, p=2.16 × 10–16.
Figure 1—figure supplement 3—source data 1. Source data used to make Figure 1—figure supplement 3.
Figure 1—figure supplement 4. Estimated number of deaths worldwide by cancer type.

Figure 1—figure supplement 4.

Both sexes and all ages are included. Data from GLOBOCAN2020; http://gco.iarc/fr/.