Phylogenetic analysis of paired breast carcinomas identifies genetic events associated with clonal recurrence and invasive progression

Kader, T; Zethoven, M; Mahale, S; Saunders, H; Tjoeka, L; Lehmann, R; Jayawardana, MW; Pang, JM; Lesche, D; Rajan, N; Semple, T; Lee, JEA; Lupat, R; Byrne, DJ; Hughes, S; Nguyen, H; Lai, S; Pechlivanis, M; Craig, O; Devereux, L; House, E; Jayasinghe, SI; Kaufmann, TL; Schwarz, RF; Green, AR; Miligy, IM; Cummings, M; Lakhani, S; Campbell, IG; Rakha, E; Fox, SB; Mann, GB; Gorringe, KL

Author(s): Kader, T; Zethoven, M; Mahale, S; Saunders, H; Tjoeka, L; Lehmann, R; Jayawardana, MW; Pang, JM; Lesche, D; Rajan, N; Semple, T; Lee, JEA; Lupat, R; Byrne, DJ; Hughes, S; Nguyen, H; Lai, S; Pechlivanis, M; Craig, O; Devereux, L; House, E; Jayasinghe, SI; Kaufmann, TL; Schwarz, RF; Green, AR; Miligy, IM; Cummings, M; Lakhani, S; Campbell, IG; Rakha, E; Fox, SB; Mann, GB; Gorringe, KL;
Details: Publication Year 2026-01,Volume 268,Issue #1,Page 1-12
Journal Title: Journal of Pathology
Publication Type: Research article
Abstract: Development of ipsilateral breast carcinoma following a diagnosis of breast ductal carcinoma in situ (DCIS) has been assumed to represent recurrence of the primary tumour. However, this may not always be the case, and it is important to determine how often such recurrences represent new tumours. Ipsilateral primary-recurrence pairs (n = 78) were sequenced to test their clonal relatedness. Shared genetic events were identified from whole exome sequencing (n = 54 pairs) using haplotype-specific copy number and phylogenetic analysis. The remaining pairs were sequenced using a targeted panel or low-coverage whole genome sequencing. We included 32 non-recurrent DCIS to compare recurrent and non-recurrent disease. We found that 7% of DCIS recurrences were non-clonal by whole exome sequencing, indicative of a new breast carcinoma. Lower resolution methods detected a higher non-clonality rate (29%). By comparing primary DCIS with their recurrence, we found that the evolution of DCIS to invasive disease was associated with increased ploidy and copy number events. TP53 mutations were enriched in DCIS with clonal recurrence compared with non-recurrent DCIS. Our results verify that de novo 'recurrent tumours' of independent origin occur in patients who may be at high risk. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Publisher: Wiley
Keywords: Humans; *Breast Neoplasms/genetics/pathology; Female; *Neoplasm Recurrence, Local/genetics/pathology; *Carcinoma, Intraductal, Noninfiltrating/genetics/pathology; Phylogeny; Mutation; Disease Progression; Exome Sequencing; Middle Aged; DNA Copy Number Variations; Neoplasm Invasiveness; Aged; *Biomarkers, Tumor/genetics; Tumor Suppressor Protein p53/genetics; Adult; breast neoplasm; clonality; ductal carcinoma in situ; phylogenetic analysis; recurrence; whole exome sequencing
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1002/path.6461
Open Access at Publisher's Site: https://doi.org/10.1002/path.6461
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-01-13 04:29:45

Last Modified: 2026-01-13 04:29:53