Atypical ductal hyperplasia is a multipotent precursor of breast carcinoma

Kader, Tanjina; Hill, Prue; Zethoven, Magnus; Goode, David L.; Elder, Kenneth; Thio, Niko; Doyle, Maria; Semple, Timothy; Sufyan, Wajiha; Byrne, David J.; Pang, Jia-Min B.; Murugasu, Anand; Miligy, Islam M; Green, Andrew R; Rakha, Emad A; Fox, Stephen B.; Mann, G. Bruce; Campbell, Ian G.; Gorringe, Kylie L.

Abstract

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.

Citation

Kader, T., Hill, P., Zethoven, M., Goode, D. L., Elder, K., Thio, N., Doyle, M., Semple, T., Sufyan, W., Byrne, D. J., Pang, J.-M. B., Murugasu, A., Miligy, I. M., Green, A. R., Rakha, E. A., Fox, S. B., Mann, G. B., Campbell, I. G., & Gorringe, K. L. (2019). Atypical ductal hyperplasia is a multipotent precursor of breast carcinoma. Journal of Pathology, 248(3), 326-338. https://doi.org/10.1002/path.5262

• Journal Article Type: Article
• Acceptance Date: Mar 4, 2019
• Online Publication Date: Mar 6, 2019
• Publication Date: Mar 6, 2019
• Deposit Date: Mar 25, 2019
• Publicly Available Date: Mar 7, 2020
• Journal: The Journal of Pathology
• Print ISSN: 0022-3417
• Electronic ISSN: 1096-9896
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 248
• Issue: 3
• Pages: 326-338
• DOI: https://doi.org/10.1002/path.5262
• Keywords: atypical ductal hyperplasia; copy number; breast cancer progression; clonal; ductal carcinoma in situ; whole genome sequencing; pre‐malignant breast lesions; benign breast disease
• Public URL: https://nottingham-repository.worktribe.com/output/1684811
• Publisher URL: https://onlinelibrary.wiley.com/doi/10.1002/path.5262
• Contract Date: Mar 29, 2019