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Identification of multiple genomic alterations and prediction of neoantigens from circulating tumor cells at the single-cell level

ABSTRACT: Circulating tumor cells (CTCs) are linked to cancer progression and poor prognosis, offering valuable genetic insights into tumors. Accurate detection of genomic alterations in CTCs is essential for improving cancer diagnosis and treatment. To address this, we develop Uniform Chromosome Conformation Capture (Uni-C), a method for profiling 3D chromatin architecture and genomic alterations at the single-cell level. Using Uni-C, we analyze CTCs from pancreatic cancer patient-derived xenograft (PDX) and spontaneous tumor mouse models. In the PDX model, integrating data from seven CTCs captures 88.7% of SNPs and INDELs, and 75.0% of structural variants present in tumor tissue. These findings indicate that variants detected in CTCs reflect tumor genomic features. Notably, we observe chromatin conformation differences between mitotic and interphase CTCs, suggesting potential markers of cell vitality. In the spontaneous tumor model, we identify driver gene mutations in CTCs and predict neoantigens, advancing early cancer detection and treatment strategies.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE267873 | GEO | 2025/06/26

REPOSITORIES: GEO

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Project description:Circulating tumor cells (CTCs) are critical in the development of distant organ tumor metastasis, and are associated with advanced cancer stage and poor patient outcome. Here, we present the first genome-wide nucleotide-level characterization of CTCs. Our single-nucleotide polymorphism (SNP) analysis in patients with melanoma involved: 1) global comparative genomic analysis of CTCs and matched regional metastases, 2) identification of key genomic aberrations in CTCs, 3) verification of these target genes in aggressive distant tumor metastases, and 4) evidence of selective expression and functional consequence of CTC-associated genes in melanomas. We report 131 aberrant loci in CTCs that are potentially pro-metastatic, and show that such expression of a 5-marker gene panel (CSMD2, CNTNAP5, FLJ14051, ADAM6, TRPM2) in melanomas confers prognostic utility. Successful treatment of melanoma requires understanding of the metastatic process and identification of patients with tumors most likely to develop aggressive metastatic disease. Melanomas are heterogeneous, and CTCs have long been recognized as vehicles for cancer spread, representing particularly aggressive tumor clones that can evolve into successful clinical metastases. Elucidation of genomic aberrations in CTCs will aid in the development of prognostic biomarkers and therapeutic strategies to target CTCs to prevent or control distant cancer spread. This study provides the first detailed genomic confirmation of the close relation between CTCs and tumor metastases, and illustrates how CTCs can be utilized as a novel approach and rational source for identification of pro-metastatic genes in cancer research. Three individual patient cohorts were utilized in the study. CNV and LOH loci were evaluated initially in metastatic melanoma patients (n=13) in a discovery cohort. SNP loci that harbored CNV/LOH in CTCs were then separately verified for: (a) presence in distant organ metastasis (AJCC Stage IV melanoma) (n=27), and (b) relevance to prognosis in regional melanoma metastasis (AJCC Stage III melanoma) (n=35). The first discovery patient cohort group was utilized for capture of CTCs, and consisted of peripheral blood mononuclear cell (PBMC) and tumor specimens from metastatic melanoma patients (n=13). CTC-related loci were verified in a second cohort of patients with Stage IV distant organ metastases (n=27), including 15 brain, 4 lung, and 8 gastrointestinal (bowel, liver) metastases. The third patient cohort consisted of early passage (<12) established melanoma cell lines derived from 35 regional melanoma metastases (Stage III) for evaluation of the prognostic utility of the CTC-associated aberrant loci.

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Identification of multiple genomic alterations and prediction of neoantigens from circulating tumor cells at the single-cell level

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