This study investigates the role of chromosomal aneuploidy in tumor development, focusing on tissue-specific patterns of copy number alterations (CNAs) in human renal and mammary epithelial cells. Using unbiased whole chromosome genetic screens combined with in vitro evolution, the researchers selected the fittest karyotypes from aneuploidized cells, revealing that tissue-specific tumor aneuploidy patterns can be modeled in the absence of driver mutations. Hi-C-based translocation mapping showed that arm-level events often arise through centromeric translocations, with higher frequency in tetraploids than diploids, contributing to increased diversity in tetraploid populations. Isogenic clonal lineages enabled the identification of pro-tumorigenic mechanisms associated with common CNAs, such as Notch signaling potentiation driving 1q gain in breast cancer. Tumors evolve through two primary mechanisms: accumulation of nucleotide-level mutations in driver genes and aneuploidy, the gain and loss of large chromosomal regions. While the oncogenic roles of driver mutations are well understood, the functions of chromosomal CNAs are less clear. Aneuploidy is costly but may provide fitness benefits under certain conditions. In vitro studies show that some CNAs can confer fitness advantages, especially in stressful environments. Aneuploidy is early in tumorigenesis and increases with disease progression. Tumor CNA patterns are tissue-specific, but common CNAs often have skewed distributions of pro- and anti-tumorigenic genes, suggesting they may promote tumorigenesis through gene dosage of drivers. Whole-genome duplication (WGD) is common in tumors and is associated with intra-tumoral heterogeneity, therapeutic resistance, and poor outcomes. WGD increases the number of copy number states and may buffer against essential gene mutations. The impact of aneuploidy and polyploidy on cellular fitness and genome evolution in the presence or absence of cancer drivers like TP53 is unclear. The study used unbiased forward genetic screens and in vitro evolution to explore the proliferative effects of chromosomal aneuploidies in human renal and mammary epithelial cells. Cancer-associated CNAs were recurrently selected in culture in a tissue-specific manner, improving growth rates in the absence of classical mutational drivers. Hi-C mapping revealed that centromeric rearrangements facilitated most chromosomal arm-level aneuploidies. Tetraploid cells exhibit increased rates of CNA acquisition, especially centromeric translocation-driven arm-level events, supporting a role for WGD in accelerating karyotype evolution during tumorigenesis. Isogenic cell line pairs generated in the screens enabled phenotypic profiling of tumor-associated CNAs, revealing candidate driver genes and pathways. The study predicts that +1q in breast cancer is driven by Notch signaling through increased expression of 1q-resident γ-secretase genes. The findings suggest that intrinsic, tissue-specificThis study investigates the role of chromosomal aneuploidy in tumor development, focusing on tissue-specific patterns of copy number alterations (CNAs) in human renal and mammary epithelial cells. Using unbiased whole chromosome genetic screens combined with in vitro evolution, the researchers selected the fittest karyotypes from aneuploidized cells, revealing that tissue-specific tumor aneuploidy patterns can be modeled in the absence of driver mutations. Hi-C-based translocation mapping showed that arm-level events often arise through centromeric translocations, with higher frequency in tetraploids than diploids, contributing to increased diversity in tetraploid populations. Isogenic clonal lineages enabled the identification of pro-tumorigenic mechanisms associated with common CNAs, such as Notch signaling potentiation driving 1q gain in breast cancer. Tumors evolve through two primary mechanisms: accumulation of nucleotide-level mutations in driver genes and aneuploidy, the gain and loss of large chromosomal regions. While the oncogenic roles of driver mutations are well understood, the functions of chromosomal CNAs are less clear. Aneuploidy is costly but may provide fitness benefits under certain conditions. In vitro studies show that some CNAs can confer fitness advantages, especially in stressful environments. Aneuploidy is early in tumorigenesis and increases with disease progression. Tumor CNA patterns are tissue-specific, but common CNAs often have skewed distributions of pro- and anti-tumorigenic genes, suggesting they may promote tumorigenesis through gene dosage of drivers. Whole-genome duplication (WGD) is common in tumors and is associated with intra-tumoral heterogeneity, therapeutic resistance, and poor outcomes. WGD increases the number of copy number states and may buffer against essential gene mutations. The impact of aneuploidy and polyploidy on cellular fitness and genome evolution in the presence or absence of cancer drivers like TP53 is unclear. The study used unbiased forward genetic screens and in vitro evolution to explore the proliferative effects of chromosomal aneuploidies in human renal and mammary epithelial cells. Cancer-associated CNAs were recurrently selected in culture in a tissue-specific manner, improving growth rates in the absence of classical mutational drivers. Hi-C mapping revealed that centromeric rearrangements facilitated most chromosomal arm-level aneuploidies. Tetraploid cells exhibit increased rates of CNA acquisition, especially centromeric translocation-driven arm-level events, supporting a role for WGD in accelerating karyotype evolution during tumorigenesis. Isogenic cell line pairs generated in the screens enabled phenotypic profiling of tumor-associated CNAs, revealing candidate driver genes and pathways. The study predicts that +1q in breast cancer is driven by Notch signaling through increased expression of 1q-resident γ-secretase genes. The findings suggest that intrinsic, tissue-specific