Whole genome doubling (WGD) occurs early in tumorigenesis and generates geneticallyunstable tetraploid cells that fuel tumor development. Cells that undergo WGD (WGD + ) must adapt to accommodate their abnormal tetraploid state; however, the nature of these adaptations, and whether they confer vulnerabilities that can subsequently be exploited therapeutically, is unclear. Using sequencing data from ~10,000 primary human cancer samples and essentiality data from ~600 cancer cell lines, we show that WGD gives rise to common genetic traits that are accompanied by unique vulnerabilities. We reveal that WGD + cells are more dependent on spindle assembly checkpoint signaling, DNA replication factors, and proteasome function than WGDcells. We also identify KIF18A, which encodes for a mitotic kinesin, as being specifically required for the viability of WGD + cells. While loss of KIF18A is largely dispensable for accurate chromosome segregation during mitosis in WGDcells, its loss induces dramatic mitotic errors in WGD + cells, ultimately impairing cell viability. Collectively, our results reveal new strategies to specifically target WGD + cancer cells while sparing the normal, nontransformed WGDcells that comprise human tissue..

47Whole genome doubling (WGD) occurs early in tumorigenesis and generates genetically 48 unstable tetraploid cells that fuel tumor development. Cells that undergo WGD (WGD + ) 49 must adapt to accommodate their abnormal tetraploid state; however, the nature of these 50 adaptations, and whether they confer vulnerabilities that can subsequently be exploited 51 therapeutically, is unclear. Using sequencing data from ~10,000 primary human cancer 52 samples and essentiality data from ~600 cancer cell lines, we show that WGD gives rise to 53 common genetic traits that are accompanied by unique vulnerabilities. We reveal that 54 WGD + cells are more dependent on spindle assembly checkpoint signaling, DNA 55 replication factors, and proteasome function than WGDcells. We also identify KIF18A, 56 which encodes for a mitotic kinesin, as being specifically required for the viability of 57 WGD + cells. While loss of KIF18A is largely dispensable for accurate chromosome 58 segregation during mitosis in WGDcells, its loss induces dramatic mitotic errors in 59 WGD + cells, ultimately impairing cell viability. Collectively, our results reveal new 60 strategies to specifically target WGD + cancer cells while sparing the normal, non-61 transformed WGDcells that comprise human tissue. 62The vast majority of human cells are diploid and numerous cell cycle controls exist to help 63 ensure that this state is maintained across successive cell divisions 1 . Despite these controls, 64 errors can occur that result in a whole genome doubling (WGD), in which a natively diploid cell 65 transitions to a tetraploid state 1-3 . It has been demonstrated that cells that have experienced a 66 WGD event (hereafter WGD + ) are oncogenic and can facilitate tumorigenesis 4,5 . WGD promotes 67 tumorigenesis in at least two ways: first, proliferating WGD + cells are genomically unstable and 68 rapidly accumulate both numerical and structural chromosomal abnormalities 5 , and second, 69 WGD + cells are better able to buffer against the negative effects of deleterious mutations and 70 ongoing chromosome instability 6-10 . Such traits enable nascent WGD + tumor cells to proliferate 71 in the presence of otherwise lethal genomic alterations while simultaneously sampling increased 72 genetic permutations, ultimately enabling phenotypic leaps that give rise to tumors 8,11 . WGD also 73 carries important clinical implications, with recent reports showing its correlation with advanced 74 metastatic disease and a worse overall prognosis 12,13 . 75 76 Given the oncogenic potential associated with WGD, tumor suppression mechanisms exist to limit 77 the proliferation of these unstable cells. WGD + cells activate both the p53 and Hippo tumor 78 suppressor pathways and are prone to apoptosis, senescence, and immune clearance [14][15][16] . WGD also 79gives rise to numerous abnormalities in cellular physiology that impair fitness 6,14,17 . Therefore, in 80 order to promote tumorigenesis, WGD + cells must adapt to overcome these barriers 5,14,18,19 . Thus, 81 while ...

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