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Identifying Multiple Genomic Abnormalities and Predicting Neoantigens from Single Tumor Cells [PRJNA1110294]

ABSTRACT: Tumors exhibit high heterogeneity due to distinct genomic aberrations in individual cells. Despite this, no methods currently exist to detect these genomic abnormalities at the single-cell level. To address this, we developed Uniform Chromosome Conformation Capture (Uni-C), an efficient method that precisely detects a variety of genomic anomalies in single cells, including single nucleotide polymorphisms (SNPs), insertions and deletions (INDELs), copy number variations (CNVs), structural variations (SVs), and focal amplifications such as extrachromosomal DNA (ecDNA) and homogeneously staining regions (HSRs). Utilizing Uni-C, we characterized varied structural variations and detailed the structure of ecDNA in circulating tumor cells (CTCs), highlighting their extensive heterogeneity. We also observed differences in chromatin conformation across CTCs in mitosis and interphase, potentially serving as markers for cell vitality. Additionally, by using genomic data from Uni-C, we detected driver gene mutations in CTCs and predicted neoantigens, significantly advancing early cancer detection and treatment strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE267872 | GEO | 2025/06/27

REPOSITORIES: GEO

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Project description:About 230 clinical trials currently explore the role of circulating tumor cell (CTC) analysis for therapy decisions, but no assays enable comprehensive molecular characterization of CTCs with diagnostic precision. We therefore combined a workflow for CTC enrichment and isolation with 100% purity with a non-random whole genome amplifiation method for single cells and applied it to 510 single CTCs and 189 leukocytes of 66 breast cancer patients. We defined a genome integrity index (GII) to identify cells suited for molecular chracterization by different molecular assay in more than 90% of single cells, such as diagnostic profiling for point mutations, gene amplifications and whole genomes of single cells. The high reliability on clinical samples enabled assessing the molecular heterogeneity of single CTCs of metastatic breast cancer patients. We readily identified therapeutically relevant genomic disparity between primary tumors and CTCs. Microheterogeneity analysis among individual CTCs uncovered preexisting cells reistsant to ERBB2 targeted therapies suggesting ongoing microevolution at late stage disease whose exploration may provide essential information for personalized treatment decisions. The analysis aimed to indentify profiles of copy number changes in genomic DNA of single circulating tumor cells (CTCs). For this, CTCs were enrched using the FDA approved CellSearch System and single-cell were isolated using the DEPArray System. Subsequently, single-cell DNA was amplified using the Ampli1 WGA Kits and subjected to single-cell aCGH analysis according to previously published protocol (Czyz ZT et al., PLoS One. 2014 Jan 21;9(1):e85907). The analysis included 38 single CTCs and 10 white blood cells (WBCs) obtained from 16 breast cancer patient. WBCs were used as controls for the analysis. In addition, four CTC cell pools were included in the analysis. This was done to show the discrepancies between the profiles of individual cells and corresponing average genomic profile of CTCs in a patient material (cell pools), thereby demonstrating the importance of the analysis on the cell-by-cell basis. The reference sample used for all aCGH experiments consisted of a pool of four single-cell WGA products generated from WBCs of a healthy female donor.

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Identifying Multiple Genomic Abnormalities and Predicting Neoantigens from Single Tumor Cells [PRJNA1110294]

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