Abstract
Simple SummaryCirculating tumor cells (CTCs) are crucial for the identification of patients with a higher risk of relapse, including those diagnosed with breast cancer (BC). The aim of this study was to explore their molecular aspects in 11 early-stage BC patients during patient management, focusing on copy number alterations (CNAs) and exploiting a single-CTC next-generation sequencing approach. CTCs showed different degrees of aberration based on access time. Moreover, CTCs, in particular those persisting even months after tumor resection, shared CNAs with matched tumor tissue. Enrichment analyses of CNAs on CTCs highlighted peculiar aberrations, especially associated with interferon (IFN)-associated terms. The study of CTCs CNAs can provide information about the molecular mechanisms involving CTC-related processes and their survival ability in occult niches, supporting the goal of exploiting their application in patients’ surveillance and follow-up.Circulating tumor cells (CTCs) are a rare population of cells representing a key player in the metastatic cascade. They are recognized as a validated tool for the identification of patients with a higher risk of relapse, including those diagnosed with breast cancer (BC). However, CTCs are characterized by high levels of heterogeneity that also involve copy number alterations (CNAs), structural variations associated with gene dosage changes. In this study, single CTCs were isolated from the peripheral blood of 11 early-stage BC patients at different time points. A label-free enrichment of CTCs was performed using OncoQuick, and single CTCs were isolated using DEPArray. Libraries were prepared from single CTCs and DNA extracted from matched tumor tissues for a whole-genome low-coverage next-generation sequencing (NGS) analysis using the Ion Torrent S5 System. The analysis of the CNA burden highlighted that CTCs had different degrees of aberration based on the time point and subtype. CTCs were found even six months after surgery and shared CNAs with matched tumor tissue. Tumor-associated CNAs that were recurrent in CTCs were patient-specific, and some alterations involved regions associated with BC and survival (i.e., gains at 1q21-23 and 5p15.33). The enrichment analysis emphasized the involvement of aberrations of terms, associated in particular with interferon (IFN) signaling. Collectively, our findings reveal that these aberrations may contribute to understanding the molecular mechanisms involving CTC-related processes and their survival ability in occult niches, supporting the goal of exploiting their application in patients’ surveillance and follow-up.
Highlights
Circulating tumor cells (CTCs) constitute the leukemic phase of a solid tumor
The only Food and Drug Administration (FDA)-approved CTC assay applied in a clinical setting with a prognostic purpose for several advanced tumors in breast cancer (BC) consists in the detection and enumeration of CTCs using the CellSearch system [7]
Jaccard Index (JI) is a measure of similarity, which we computed as the ratio of shared-to-all aberrations between single CTCs and lymphocytes, which we considered as a reference normal chromosomal set
Summary
Circulating tumor cells (CTCs) constitute the leukemic phase of a solid tumor They have the potential to give rise to detectable metastasis [1] and to date the major cause of death in cancer patients [2]. Their identification and subsequent molecular analysis, in particular at a single-cell level, provide information about the prognosis and could be useful for a selective choice for targeted therapies and therapy monitoring [3,4,5,6], enforcing the rationale of using CTCs in the clinical application of liquid biopsy approaches. Besides mammography and other instrumental tests based on symptom occurrence, there are no recommended tests in the follow-up of operated asymptomatic patients [8,9,10,11]
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