Synchronous ductal carcinoma in situ single cell DNA sequencing

Ductal Carcinoma in situ (DCIS) is an early stage breast cancer and nonobligatory precursor to invasive ductal cancer (IDC). Genomic evolution during invasion has been difficult to delineate in bulk tissues due to the limited number of tumor cells in the ducts and the extensive intratumor heterogeneity. To overcome these challenges, we developed Topographic Single Cell Sequencing (TSCS) combining laser-catapulting and single cell DNA sequencing to measure genomic copy number profiles from single tumor cells while preserving their spatial context. We applied TSCS to profile 1075 single cells from 10 synchronous DCIS patients, in addition to deep-exome sequencing of microdissected regions. Our data shows that genomic evolution was intraductal and gave rise to multiple clonal subpopulations that escaped the ducts and expanded to form invasive legions. Our data suggests that invasive clones are pre-programmed in the ducts, at the earliest stages of tumor progression, having implications for diagnostics and treatment of DCIS patients.