The breast pre-cancer atlas illustrates the molecular and microenvironmental diversity of ductal carcinoma in situ

Microenvironmental and molecular factors mediating the progression of Breast Ductal Carcinoma In Situ (DCIS) are not well understood, impeding the development of prevention strategies and the safe testing of treatment de-escalation. We addressed methodological barriers and characterized the mutational, transcriptional, histological, and microenvironmental landscape across 85 multiple microdissected regions from 39 cases. Most somatic alterations, including whole-genome duplications, were clonal, but genetic divergence increased with physical distance. Phenotypic and subtype heterogeneity was frequently associated with underlying genetic heterogeneity and regions with low-risk features preceded those with high-risk features according to the inferred phylogeny. B- and T-lymphocytes spatial analysis identified three immune states, including an epithelial excluded state located preferentially at DCIS regions, and characterized by histological and molecular features of immune escape, independently from molecular subtypes. Such breast pre-cancer atlas with uniquely integrated observations will help scope future expansion studies and build finer models of outcomes and progression risk.

Automated summary

The progression of Breast Ductal Carcinoma In Situ (DCIS) is influenced by microenvironmental and molecular factors, which are not well understood. This study analyzed multiple microdissected regions from 39 cases and characterized the mutational, transcriptional, histological, and microenvironmental landscape. Genetic divergence increased with physical distance and phenotypic and subtype heterogeneity was associated with underlying genetic heterogeneity. The study also identified an immune escape state with histological and molecular features located preferentially at DCIS regions.