The genetic architecture of breast papillary lesions as a predictor of progression to carcinoma

Thio, Niko; Kader, Tanjina; Elder, Kenneth; Zethoven, Magnus; Semple, Timothy; Hill, Prue; Goode, David L; Cheasley, Dane; Rowley, Simone M; Byrne, David J; Miligy, Islam M; Pang, Jia-Min; Green, Andrew R; Rakha, Emad A; Fox, Stephen B; Mann, G Bruce; Campbell, Ian G; Gorringe, Kylie L

Abstract

Intra-ductal papillomas (IDP) are challenging breast findings because of their variable risk of progression to malignancy. The molecular events driving IDP development and genomic features of malignant progression are poorly understood. In this study, genome-wide CNA and/or targeted mutation analysis was performed on 44 cases of IDP, of which 20 cases had co-existing ductal carcinoma in situ (DCIS), papillary DCIS or invasive ductal carcinoma (IDC). CNA were rare in pure IDP, but 69% carried an activating PIK3CA mutation. Among the synchronous IDP cases, 55% (11/20) were clonally related to the synchronous DCIS and/ or IDC, only one of which had papillary histology. In contrast to pure IDP, PIK3CA mutations were absent from clonal cases. CNAs in any of chromosomes 1, 16 or 11 were significantly enriched in clonal IDP lesions compared to pure and non-clonal IDP. The observation that 55% of IDP are clonal to DCIS/IDC indicates that IDP can be a direct precursor for breast carcinoma, not limited to the papillary type. The absence of PIK3CA mutations and presence of CNAs in IDP could be used clinically to identify patients at high risk of progression to carcinoma.

Citation

Thio, N., Kader, T., Elder, K., Zethoven, M., Semple, T., Hill, P., …Gorringe, K. L. (2020). The genetic architecture of breast papillary lesions as a predictor of progression to carcinoma. npj Breast Cancer, 6, Article 9. https://doi.org/10.1038/s41523-020-0150-6

• Journal Article Type: Article
• Acceptance Date: Feb 13, 2020
• Online Publication Date: Mar 12, 2020
• Publication Date: Mar 12, 2020
• Deposit Date: Jan 10, 2020
• Publicly Available Date: Mar 16, 2020
• Journal: npj Breast Cancer
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 6
• Article Number: 9
• DOI: https://doi.org/10.1038/s41523-020-0150-6
• Keywords: atypical papillary lesions, benign papilloma, copy number alteration, breast cancer progression, clonal relationship, breast neoplasms, ductal carcinoma in situ, mammographic screening, next generation sequencing, low coverage whole genome sequencing, SNP
• Public URL: https://nottingham-repository.worktribe.com/output/3702137
• Publisher URL: https://www.nature.com/articles/s41523-020-0150-6