The hallmark signatures based on gene expression capture core cancer processes. Through a pan-cancer analysis, we describe the overview of hallmark signatures across tumor types/subtypes and reveal significant relationships between these signatures and genetic alterations. TP53 mutation exerts diverse changes, including increased proliferation and glycolysis, which are closely mimicked by widespread copy-number alterations. Hallmark signature and copy-number clustering identify a cluster of squamous tumors and basal-like breast and bladder cancers with elevated proliferation signatures, frequent TP53 mutation, and high aneuploidy. In these basal-like/squamous TP53-mutated tumors, a specific and consistent spectrum of copy-number alterations is preferentially selected prior to whole-genome duplication. Within Trp53-null breast cancer mouse models, these copy-number alterations spontaneously occur and recapitulate the hallmark signature changes observed in the human condition. Together, our analysis reveals intertumor and intratumor heterogeneity of the hallmark signatures, uncovering an oncogenic program induced by TP53 mutation and select aneuploidy events to drive a worsened prognosis.Significance:Our data demonstrate that TP53 mutation and a resultant selected pattern of aneuploidies cause an aggressive transcriptional program including upregulation of glycolysis signature with prognostic implications. Importantly, basal-like breast cancer demonstrates genetic and/or phenotypic changes closely related to squamous tumors including 5q deletion that reveal alterations that could offer therapeutic options across tumor types regardless of tissue of origin.