Landscape of Genetic Alterations Underlying Hallmark Signature Changes in Cancer Reveals TP53 Aneuploidy-driven Metabolic Reprogramming

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 re-lationships 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. Hall -mark 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 signa-tures, 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 se-lected 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 pheno-typic 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.

Automated summary

Hallmark signatures based on gene expression capture core cancer processes and have significant relationships with genetic alterations. TP53 mutation leads to diverse changes, including increased proliferation and glycolysis, similar to widespread copy-number alterations. Basal-like breast and bladder cancers demonstrate specific genetic and phenotypic changes related to squamous tumors, indicating potential therapeutic options across tumor types. These findings highlight the heterogeneity of hallmark signatures and suggest an oncogenic program induced by TP53 mutation and selected aneuploidy events.