DCIS is one of the most common breast cancer diagnoses; however, it remains difficult to manage. Although considered a non-invasive precursor, most cases will not progress to invasive cancer if left untreated. Current pathology tools cannot reliably separate indolent disease from lesions with true malignant potential, leading to overtreatment with surgery or radiotherapy.
To address this gap, researchers from the PRECISION consortium performed high-depth whole genome sequencing on 113 DCIS lesions. “Using a highly innovative method combining microdissection and whole genome sequencing, we studied very small DCIS lesions in depth to decipher their genomic landscape in great detail,” says Esther Lips. The research involved an international collaboration across the Netherlands, United Kingdom, and United States. Major contributions came from the Netherlands Cancer Institute (NKI) and Serena Nik-Zainal at the University of Cambridge. Genomic profiles were compared with invasive and metastatic breast cancer genomes to map early evolutionary changes.
The analysis identified regions of the genome prone to structural rearrangements, termed SHOREs (Sites of Hotspot Rearrangements and Evolution). These regions are vulnerable to DNA breakage during transcription-replication conflicts, when DNA reading and copying machinery collide. The findings suggest genomic disruption can arise early, before invasion.
Nearly half of lesions (46%) showed molecular features linked to aggressive evolution, including extrachromosomal DNA (ecDNA), circular DNA fragments that amplify cancer-driving genes. Some lesions classified as intermediate-grade under microscopy already showed high-risk genomic features, highlighting a disconnect between histology and tumor biology.
“We show for the very first time at this level that DCIS can exhibit highly complex genomic changes even before invasion occurs,” says Esther Lips.
While not yet ready for clinical use, the findings provide a genomic roadmap for future DCIS classification. By identifying early markers such as SHOREs and ecDNA, the study supports efforts to distinguish lesions suitable for surveillance from those requiring treatment. A more precise, biology-driven approach could reduce unnecessary intervention while ensuring appropriate care for higher-risk disease.
PRECISION is a major international research project on DCIS funded by Cancer Research UK and the Dutch Cancer Society as part of Cancer Grand Challenges – a global funding initiative co-founded by Cancer Research UK and the National Cancer Institute in the US. It is led by Jelle Wesseling.
Research at the NKI is financially supported by KWF Dutch Cancer Society and the AVL Foundation.
