Spatially Discontinuous Mutation Topographies in Ductal Carcinoma In Situ Reveal Noncompetitive Growth Dynamics.

Abstract

Preinvasive breast cancer, or ductal carcinoma in situ (DCIS), shares many morphologic and genomic features with invasive breast cancer, yet most DCIS tumors remain indolent over decades. In this study, we performed spatial analyses of somatic mutation patterns in 18 DCIS tumors to infer the underlying growth dynamics. Experimental data combined with mathematical models and Bayesian computation revealed a growth model that mimics the cellular dynamics of branching morphogenesis, which governs normal mammary gland development during puberty. Unlike a traditional model of clonal evolution, this noncompetitive growth model allowed for extensive DCIS spread without the selective pressures of subclone competition that promote the emergence of invasive phenotypes. This finding provides a framework to understand the biological basis for the limited progression of DCIS and adds rationale for ongoing clinical efforts to reduce DCIS overtreatment. The spatial mutation landscape in ductal carcinoma in situ supports a noncompetitive growth model mirroring normal branching morphogenesis, which has implications for managing low-risk patients and for cancers in other branching organs. This article is part of a special series: Driving Cancer Discoveries with Computational Research, Data Science, and Machine Learning/AI .