Genomic profiling defines variable clonal relatedness between invasive breast cancer and primary ductal carcinoma in situ

Esther H. Lips; Tapsi Kumar; Anargyros Megalios; Lindy L. Visser; Michael Sheinman; Angelo Fortunato; Vandna Shah; Marlous Hoogstraat; Emi Sei; Diego Mallo; Maria Roman-Escorza; Ahmed A. Ahmed; Mingchu Xu; Alexandra W. van den Belt‐Dusebout; Wim Brugman; Tod D. Casasent; Karen Clements; Helen Ruth Davies; Liping Fu; Anita E. Grigoriadis; Timothy Hardman; Lorraine M. King; Marielle Krete; Petra Kristel; Michiel de Maaker; Carlo C. Maley; Jeffrey R. Marks; Brian A. Menegaz; Lennart Mulder; Frank Nieboer

doi:10.1038/s41588-022-01082-3

Genetic & Genomic MedicineNature GeneticsJun 1, 2022

Peer-reviewed journal article

Genomic profiling defines variable clonal relatedness between invasive breast cancer and primary ductal carcinoma in situ

Esther H. Lips iD, Tapsi Kumar iD, Anargyros Megalios iD, Lindy L. Visser iD, Michael Sheinman iD, Angelo Fortunato iD, Vandna Shah iD, Marlous Hoogstraat iD, Emi Sei iD, Diego Mallo iD, Maria Roman-Escorza iD, Ahmed A. Ahmed iD, Mingchu Xu, Alexandra W. van den Belt‐Dusebout iD, Wim Brugman iD, Tod D. Casasent iD, Karen Clements iD, Helen Ruth Davies iD, Liping Fu iD, Anita E. Grigoriadis iD, Timothy Hardman, Lorraine M. King iD, Marielle Krete, Petra Kristel, Michiel de Maaker, , Elinor J. Sawyer iD

Abstract

Pure ductal carcinoma in situ (DCIS) is being diagnosed more frequently through breast screening programmes and is associated with an increased risk of developing invasive breast cancer. We assessed the clonal relatedness of 143 cases of pure DCIS and their subsequent events using a combination of whole exome, targeted and copy number sequencing, supplemented by single cell analysis. Unexpectedly, 18% of all invasive events after DCIS were clonally unrelated to the primary DCIS. Single cell sequencing of selected pairs confirmed our findings. In contrast, synchronous DCIS and invasive disease (n=44) were almost always (93%) clonally related. This challenges the dogma that almost all invasive events after DCIS represent invasive transformation of the initial DCIS and suggests that DCIS could be an independent risk factor for developing invasive disease as well as a precursor lesion. Our findings support a paradigm shift that confirms a more complex role for DCIS than previously recognized, and that the future management of DCIS should take into account both the precursor and risk factor implications of this diagnosis.

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