Genomic profiling reveals heterogeneous populations of ductal carcinoma in situ of the breast

A substantial number of cases of ductal carcinoma in situ (DCIS) of the breast will never progress to invasive ductal carcinoma (IDC), indicating they are overtreated under the current criteria. Although various candidate markers are available, the relevant markers for delineating the risk categories have not been established. In this study, we analyzed of the integrated clinical features of 431 cases of DCIS followed by deep sequence analyses in a 21-case discovery cohort and a 72-case validation cohort. We identified the five most critical markers of the aggressiveness of DCIS: age <45 years, HER2 amplification, GATA3 mutation positivity, PIK3CA mutation negativity, and PgR protein negativity. Spatial transcriptome and single-cell DNA sequencing further revealed that GATA3 dysfunction, but not PIK3CA mutation, upregulates EMT, invasion, and angiogenic pathways followed by PgR downregulation. These results reveal the existence of heterogeneous populations of DCIS and provide predictive markers for classifying DCIS and optimizing treatment.