Pan-urologic cancer genomic subtypes that transcend tissue of origin.

Abstract

Urologic cancers include cancers of the bladder, kidney, prostate, and testes, with common molecular features spanning different types. Here, we show that 1954 urologic cancers can be classified into nine major genomic subtypes, on the basis of multidimensional and comprehensive molecular characterization (including DNA methylation and copy number, and RNA and protein expression). Tissue dominant effects are first removed computationally in order to define these subtypes, which reveal common processes-reflecting in part tumor microenvironmental influences-driving cellular behavior across tumor lineages. Six of the subtypes feature a mixture of represented cancer types as defined by tissue or cell of origin. Differences in patient survival and in the manifestation of specific pathways-including hypoxia, metabolism, NRF2-ARE, Hippo, and immune checkpoint-can further distinguish the subtypes. Immune checkpoint markers and molecular signatures of macrophages and T cell infiltrates are relatively high within distinct subsets of each cancer type studied. The pan-urologic cancer genomic subtypes would facilitate information sharing involving therapeutic implications between tissue-oriented domains.Urological cancers have disparate tissues and cells of origin but share many molecular features. Here, the authors use multidimensional and comprehensive molecular characterization to classify urological cancers into nine major genomic subtypes, highlighting potential therapeutic targets.