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In modern cancer biology, Hanahan and Weinberg's classic depiction of the Hallmarks of Cancer serves as a heuristic for understanding malignant phenotypes [1]. Genetic determinants of these phenotypes promote cancer induction and progression, and these mutations drive current approaches to understanding and treating cancer. Meanwhile, for over a century, pathologists have noted that profound alterations of nuclear structure accompany transformation, integrating these changes into diagnostic classifications (Figure 1). Nevertheless, the relationship of nuclear organization to malignant phenotypes has lagged. Recent advances yield profound insight into the 3D genome's relationship with cancer phenotypes, suggesting that spatial genome organization influences many, if not all, of these malignant features. Here, we highlight recent discoveries elucidating connections between 3D genome organization and cancer phenotypes.