Aneuploidy-induced cancer vulnerability to mitotic checkpoint inhibition

This repo contains some of the analysis done for the paper Aneuploidy-induced cancer vulnerability to mitotic checkpoint inhibition by Cohen-Sharir et al.

• link to paper in Nature: https://www.nature.com/articles/s41586-020-03114-6
• link to bioRxiv: https://www.biorxiv.org/content/10.1101/2020.06.18.159038v1.full

FIGURE X and Supplementary Extended Data Figure X notebooks match up with the published version of the manuscript

Brief description of the figures and code availability:

Figure 1: Differential sensitivity of aneuploid cancer cells to inhibition of the spindle assembly checkpoint.

• code available for 1b, 1d-h (Figure 1.ipynb)

Figure 2: The effect of aneuploidy on cellular sensitivity to SACi in isogenic human cell lines.
Figure 3: Transcriptional, cellular and karyotypic characterization of SACi in aneuploid cells.
Figure 4: Altered spindle geometry and dynamics, and increased dependency on the mitotic kinesin KIF18A, in aneuploid cancer cells.

• code available for 4e (Figure 4.ipynb)

Extended Data Figure 1: Increased sensitivity of aneuploid cancer cells to genetic inhibition of the spindle assembly checkpoint.

• code available for 1b-c, 1g-k (Extended Data Figure 1.ipynb)

Extended Data Figure 2: Genomic and phenotypic features associated with the degree of aneuploidy in human cancer cell lines.

• code available for 2a-e (Extended Data Figure 2.ipynb)

Extended Data Figure 3: Increased sensitivity of aneuploid cancer cells to SACi remains significant when associated genomic and phenotypic features are controlled for.

• code available for 3a-i (Extended Data Figure 3.ipynb)

Extended Data Figure 4: Reduced sensitivity of aneuploid cancer cells to chemical inhibition of the spindle assembly checkpoint

• code available for 4a-e (Extended Data Figure 4.ipynb)

Extended Data Figure 5: Isogenic model systems of near-diploid and aneuploid cell lines.
Extended Data Figure 6: The effect of aneuploidy on cellular sensitivity to SACi in isogenic human cell lines.
Extended Data Figure 7: Time-dependent increased sensitivity of aneuploid cancer cells to genetic and chemical SACi.
Extended Data Figure 8: Transcriptional and cellular characterization of SACi in aneuploid cells.
Extended Data Figure 9: Increased sensitivity of aneuploid cancer cells to perturbation of the mitotic kinesin KIF18A.

• code available for 9f-k (Extended Data Figure 9.ipynb)

Extended Data Figure 10: Increased sensitivity of aneuploid cells to KIF18A inhibition.

• code available for 10a-i (Extended Data Figure 10.ipynb)

Brief description of the tables and code availability:

Supplementary Table 1: Chromosome-arm copy number calls and aneuploidy scores for 997 human cancer cell lines.

• "make_CCLE_arm_calls.R" takes the CCLE2 published ABSOLUTE data as input and calls the number of arm-level CNAs for each cell line (anueploidy score).
• "make_aneuploidy_calls.R" takes that output and calls the 'many_arm_events' column based on the upper and lower quantiles.

Supplementary Table 2: Genetic dependencies of highly-aneuploid cancer cells.

• code for Limma runs found in Limma folder. Files: limma_drive.R and limma_achilles.R for Drive and Achilles, respectively

Supplementary Table 3: Functional annotation enrichment analysis of aneuploidy- associated genetic dependencies.
Supplementary Table 4: mRNA expression differences between near-euploid and highly- aneuploid cancer cells.

• code for Limma run found in expression/limma_differential_expression.R

Supplementary Table 5: Chemical sensitivities of highly-aneuploid cancer cells.

• code for Limma runs found in limma/drug_comparisons. Files: using_limma_CTD.R, using_limma_GDSC.R, using_limma_prism.R

Supplementary Table 6: Cancer cell line sensitivity to the SAC inhibitor reversine.
Supplementary Table 7: Gene expression profiles of HCT116 and HPT cells exposed to SAC inhibitors.
Supplementary Table 8: Association between aneuploidy levels and KIF18A mRNA and protein expression levels.

Code written by: Mariya Kazachkova and James McFarland (contact: jmmcfarl -at- broadinstitute.org)