Atypical ductal hyperplasia is a multipotent precursor of breast carcinoma. Homo sapiens

The current model for breast cancer progression proposes independent “low-grade (LG) like”and “high-grade (HG) like” pathways but lacks a known precursor to HG cancer. We appliedlow coverage whole genome sequencing to atypical ductal hyperplasia (ADH) with andwithout carcinoma to shed light on breast cancer progression. 14/20 isolated ADH casesharboured at least one copy number alteration (CNA), but had fewer aberrations than LG orHG ductal carcinoma in situ (DCIS). ADH carried more HG-like CNA than LG DCIS (eg. 8qgain). Correspondingly, 64% (7/11) of ADH cases with synchronous HG carcinoma wereclonally related, similar to LG carcinoma (67%, 6/9). This study represents a significant shiftin our understanding of breast cancer progression, with ADH as a common precursor lesionto the independent “low-grade like” and “high-grade like” pathways. These data suggest thatADH can be a precursor of HG breast cancer and that LG and HG carcinomas can evolvefrom a similar ancestor lesion. We propose that although LG DCIS may be committed to aLG molecular pathway, ADH may remain multipotent, progressing to either LG or HGcarcinoma. This multipotent nature suggests that some ADH could be more clinicallysignificant than LG DCIS, requiring biomarkers for personalising management.