This study investigates the selective advantages of chromosomal copy number alterations (CNA) in human epithelial cells, specifically renal and mammary epithelial cells, using unbiased whole chromosome genetic screens and in vitro evolution. The researchers selected the fittest karyotypes from aneuploidized cells, modeling tissue-specific tumor aneuploidy patterns in patient cohorts without driver mutations. Hi-C mapping revealed that arm-level events often emerged in multiples of two via centromeric translocations and were more frequent in tetraploids, contributing to increased diversity in evolving tetraploid populations. Isogenic clonal lineages enabled the elucidation of pro-tumorigenic mechanisms associated with common CNA alterations, such as the potentiation of Notch signaling through increased expression of γ-secretase genes, which drives 1q gain in breast cancer. The study suggests that intrinsic, tissue-specific proliferative effects underlie tumor copy number patterns in cancer.This study investigates the selective advantages of chromosomal copy number alterations (CNA) in human epithelial cells, specifically renal and mammary epithelial cells, using unbiased whole chromosome genetic screens and in vitro evolution. The researchers selected the fittest karyotypes from aneuploidized cells, modeling tissue-specific tumor aneuploidy patterns in patient cohorts without driver mutations. Hi-C mapping revealed that arm-level events often emerged in multiples of two via centromeric translocations and were more frequent in tetraploids, contributing to increased diversity in evolving tetraploid populations. Isogenic clonal lineages enabled the elucidation of pro-tumorigenic mechanisms associated with common CNA alterations, such as the potentiation of Notch signaling through increased expression of γ-secretase genes, which drives 1q gain in breast cancer. The study suggests that intrinsic, tissue-specific proliferative effects underlie tumor copy number patterns in cancer.