Abstract
Circulating tumor cells (CTCs) provide an accessible tool for investigating tumor heterogeneity and cell populations with metastatic potential. Although an in-depth molecular investigation is limited by the extremely low CTC count in circulation, significant progress has been made recently in single-cell analytical processes. Indeed, CTC monitoring through molecular and functional characterization may provide an understanding of genomic instability (GI) molecular mechanisms, which contribute to tumor evolution and emergence of resistant clones. In this review, we discuss the sources and consequences of GI seen through single-cell analysis of CTCs in different types of tumors. We present a detailed overview of chromosomal instability (CIN) in CTCs assessed by fluorescence in situ hybridization (FISH), and we reveal utility of CTC single-cell sequencing in identifying copy number alterations (CNA) oncogenic drivers. We highlight the role of CIN in CTC-driven metastatic progression and acquired resistance, and we comment on the technical obstacles and challenges encountered during single CTC analysis. We focus on the DNA damage response and depict DNA-repair-related dynamic biomarkers reported to date in CTCs and their role in predicting response to genotoxic treatment. In summary, the suggested relationship between genomic aberrations in CTCs and prognosis strongly supports the potential utility of GI monitoring in CTCs in clinical risk assessment and therapeutic choice.
Highlights
Circulating tumor cells (CTC), present in peripheral blood of patients with cancers, are released from spatially distinct metastatic sites and primary tumor and may provide a comprehensive genomic picture of tumor content
A study in castration-resistance prostate cancer (CRPC) showed that ERG oncogene status was maintained in CTCs, while significant genetic heterogeneity was observed in AR copy number gain and PTEN loss
We showed that patients monitored at the early stage of crizotinib treatment presented significant correlation between dynamic evolution of the amount of ALK copy number gained in CTCs and PFS, suggesting that increased chromosomal instability (CIN) in CTCs may be associated with a worse outcome in ALK-rearranged NSCLC [41]
Summary
Circulating tumor cells (CTC), present in peripheral blood of patients with cancers, are released from spatially distinct metastatic sites and primary tumor and may provide a comprehensive genomic picture of tumor content. Recent data on single CTC genomic analysis revealed the wide heterogeneity of CTCs, emphasizing the potential clinical utility of single CTC sequencing in identifying resistant clones that are arguably an important subset of cancer cells to target and eradicate. Oncogenic mutations as well as large-scale genomic alterations, copy number changes, DNA damage repair deficiencies or cell cycle perturbations may serve as an origin of GI and subsequent tumor heterogeneity. 2. Genomic Instability, More Than a Hallmark of Cancer Over the past few years, genomic studies have demonstrated the complex and heterogeneous landscape of cancer and its potential impact on treatment resistance and metastasis development. Alterations in the DNA damage response (DDR), endogenous and oncogene-induced replication stress or cell division deregulation promote GI in cancer (Figure 1)
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