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 applied
low coverage whole genome sequencing to atypical ductal hyperplasia (ADH) with and
without carcinoma to shed light on breast cancer progression. 14/20 isolated ADH cases
harboured at least one copy number alteration (CNA), but had fewer aberrations than LG or
HG ductal carcinoma in situ (DCIS). ADH carried more HG-like CNA than LG DCIS (eg. 8q
gain). Correspondingly, 64% (7/11) of ADH cases with synchronous HG carcinoma were
clonally related, similar to LG carcinoma (67%, 6/9). This study represents a significant shift
in our understanding of breast cancer progression, with ADH as a common precursor lesion
to the independent “low-grade like” and “high-grade like” pathways. These data suggest that
ADH can be a precursor of HG breast cancer and that LG and HG carcinomas can evolve
from a similar ancestor lesion. We propose that although LG DCIS may be committed to a
LG molecular pathway, ADH may remain multipotent, progressing to either LG or HG
carcinoma. This multipotent nature suggests that some ADH could be more clinically
significant than LG DCIS, requiring biomarkers for personalising management. Less...