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

a, Copy number profiles of 5 representative breast cancer cell lines from the highly-aneuploid cell line group (top quartile of AS) and 5 representative breast cancer cell lines from the near-euploid cell line group (bottom quartile of AS). b, A volcano plot showing the differential genetic dependencies between the near-euploid and highly-aneuploid cancer cell lines (top vs. bottom quartiles), based on the genome-wide DRIVE RNAi screen⁴. BUB1B and MAD2, core members of the SAC, are highlighted in red. c, A Venn diagram showing the overlap of the differentially-dependent genes (q<0.25) between the Achilles and DRIVE RNAi screens. ****P = 1e-16, two-tailed Fisher’s exact test. d, The pathways enriched in the list of genes that are more essential in near-euploid than in highly-aneuploid cancer cell lines (effect size <-0.1, q < 0.1) in the DRIVE RNAi screen, based on DAVID functional annotation enrichment analysis⁵⁹. The full list is available in Supplementary Table 3. *, Benjamini-corrected p-value <0.1; one-tailed Fisher’s Exact Test. e, The sensitivity of near-euploid and highly-aneuploid cancer cell lines to the knockdown of BUB1B (left) and MAD2 (right) in the DRIVE RNAi screen. The more negative a value, the more essential the gene is in that cell line. ****P = 2e-06 and P = 1e-04 for BUB1B and MAD2, respectively; two-tailed t-test. f, A volcano plot showing the differential genetic dependencies between the near-euploid and highly-aneuploid cancer cell lines (top vs. bottom 10% of cell lines), based on the genome-wide DRIVE RNAi screen⁴. BUB1B, MAD2 and KIF18A are highlighted in red. g, The sensitivity of near-euploid and highly-aneuploid cancer cell lines to the knockdown of BUB1B (left) and MAD2 (right) in the DRIVE RNAi screen (top vs. bottom 10% of cell lines). The more negative a value, the more essential the gene is in that cell line. *P = 0.037; ***P = 5e-04; two-tailed t-test. h, Comparison of protein expression levels of BUB1B (left) and MAD2 (right) between near-euploid and highly-aneuploid cancer cell lines. n.s., P > 0.05; **P = 0.001; for BUB1B and MAD2, respectively; two-tailed t-test. i, The correlations between the mRNA expression levels of BUB1B (top) and MAD2 (bottom) and the genetic dependency on these genes in the Achilles (left) and DRIVE (right) RNAi screens. Spearman’s ρ = 0.36 (P = 3e-08), 0.31 (P = 2e-06), 0.26 (P = 4e-04) and 0.40 (P = 2e-08), respectively. j, The correlations between the protein expression levels of BUB1B (top) and MAD2 (bottom) and the genetic dependency on these genes in the Achilles (left) and DRIVE (right) RNAi screens. Spearman’s ρ = 0.11 (P = 0.09), 0.26 (P = 4e-05), 0.14 (P = 0.016) and 0.24 (P = 5e-05), respectively. k, The mRNA expression levels of BUB1B (left) and MAD2 (right) in near-euploid and highly-aneuploid cancer cell lines across multiple cell lineages. *P < 0.05; two-tailed t-test.