Tracking clonal evolution during treatment in ovarian cancer using cell-free DNA

• 成果类型: Article
• 署名作者: Williams, Marc J.; Vazquez-Garcia, Ignacio; Tam, Grittney; Wu, Michelle; Varice, Nancy; Havasov, Eliyahu; Shi, Hongyu; Al-Rawi, Duaa H.; Satas, Gryte; Lees, Hannah J.; Lee, Jake June-Koo; Myers, Matthew A.; Zatzman, Matthew; Rusk, Nicole; Ali, Emily; Shah, Ronak H.; Berger, Michael F.; Mohibullah, Neeman; Lakhman, Yulia; Chi, Dennis S.; Abu-Rustum, Nadeem R.; Aghajanian, Carol; Mcpherson, Andrew; Zamarin, Dmitriy; Loomis, Brian; Weigelt, Britta; Friedman, Claire F.; Shah, Sohrab P.
• 署名单位: Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Columbia University; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Icahn School of Medicine at Mount Sinai; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09580-0
• 发表日期: 2025-11-20
• 关键词: breast

摘要

Emergence of drug resistance is the main cause of therapeutic failure in patients with high-grade serous ovarian cancer (HGSOC)1. To study drug resistance in patients, we developed CloneSeq-SV, which combines single-cell whole-genome sequencing2 with targeted deep sequencing of clone-specific genomic structural variants in time-series cell-free DNA. CloneSeq-SV exploits tumour clone-specific structural variants as highly sensitive endogenous cell-free DNA markers, enabling the relative abundance measurements and evolutionary analysis of co-existing clonal populations over the therapeutic time course. Here, using this approach, we studied 18 patients with HGSOC over a multi-year period from diagnosis to recurrence and showed that drug resistance typically arose from selective expansion of a single or small subset of clones present at diagnosis. Drug-resistant clones frequently showed interpretable and distinctive genomic features, including chromothripsis, whole-genome doubling, and high-level amplifications of oncogenes such as CCNE1, RAB25, MYC and NOTCH3. Phenotypic analysis of matched single-cell RNA sequencing data3 indicated pre-existing and clone-specific transcriptional states such as upregulation of epithelial-to-mesenchymal transition and VEGF pathways, linked to drug resistance. In one notable case, clone-specific ERBB2 amplification affected the efficacy of a secondary targeted therapy with a positive patient outcome. Together, our findings indicate that drug-resistant states in HGSOC pre-exist at diagnosis, leading to positive selection and reduced clonal complexity at relapse. We suggest these findings motivate investigation of evolution-informed adaptive treatment regimens to ablate drug resistance in future HGSOC studies.