Genomic analysis defines clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancer

• Published in: Nature genetics Vol. 54; no. 6; pp. 850 - 860
• Main Authors: Lips, Esther H., Kumar, Tapsi, Megalios, Anargyros, Visser, Lindy L., Sheinman, Michael, Fortunato, Angelo, Shah, Vandna, Hoogstraat, Marlous, Sei, Emi, Mallo, Diego, Roman-Escorza, Maria, Ahmed, Ahmed A., Xu, Mingchu, van den Belt-Dusebout, Alexandra W., Brugman, Wim, Casasent, Anna K., Clements, Karen, Davies, Helen R., Fu, Liping, Grigoriadis, Anita, Hardman, Timothy M., King, Lorraine M., Krete, Marielle, Kristel, Petra, de Maaker, Michiel, Maley, Carlo C., Marks, Jeffrey R., Menegaz, Brian A., Mulder, Lennart, Nieboer, Frank, Nowinski, Salpie, Pinder, Sarah, Quist, Jelmar, Salinas-Souza, Carolina, Schaapveld, Michael, Schmidt, Marjanka K., Shaaban, Abeer M., Shami, Rana, Sridharan, Mathini, Zhang, John, Stobart, Hilary, Collyar, Deborah, Nik-Zainal, Serena, Wessels, Lodewyk F. A., Hwang, E. Shelley, Navin, Nicholas E., Futreal, P. Andrew, Thompson, Alastair M., Wesseling, Jelle, Sawyer, Elinor J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2022; Nature Publishing Group
• Subjects: 631/208/514/1948; 631/67/1347; Agriculture; Animal Genetics and Genomics; Biomarkers; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer Research; Carcinoma, Ductal, Breast - genetics; Carcinoma, Intraductal, Noninfiltrating - genetics; Carcinoma, Intraductal, Noninfiltrating - pathology; Disease; DNA sequencing; Female; Gene Function; Genomic analysis; Genomics; Human Genetics; Humans; Invasiveness; Mammography; Mutation; Neoplasm Recurrence, Local - genetics; Patients; Questions; Radiation therapy; Risk assessment; Tumor cells; Tumors
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-022-01082-3

Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5–10%) of DCIS patients develop subsequent invasive disease. A fundamental biologic question is whether the invasive disease arises from tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial DCIS lesion and paired invasive recurrent tumors in 95 patients together with single-cell DNA sequencing in a subset of cases. Our data show that in 75% of cases the invasive recurrence was clonally related to the initial DCIS, suggesting that tumor cells were not eliminated during the initial treatment. Surprisingly, however, 18% were clonally unrelated to the DCIS, representing new independent lineages and 7% of cases were ambiguous. This knowledge is essential for accurate risk evaluation of DCIS, treatment de-escalation strategies and the identification of predictive biomarkers. A genomic analysis of ductal carcinoma in situ (DCIS) samples with matched ipsilateral invasive breast cancer recurring later shows that around 18% of tumors were unrelated to the DCIS, and had distinct clonal origins.