Genomic Instability in Circulating Tumor Cells

Freitas, Monique Oliveira; Gartner, John G.; Rangel‐Pozzo, Aline; Mai, Sabine

doi:10.3390/cancers12103001

Cited by 11 publications

(7 citation statements)

References 151 publications

(261 reference statements)

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“…However, our data showed that sSMC cells have higher instability and a different cell cycle dynamic compared with normal cells. We also showed that these cells exhibit telomeric instability, which enables development of tumors and progression of tumor cells to adapt selectively to different environmental pressures resulting in intratumoral cell heterogeneity ( 9 ).…”

Section: Discussionmentioning

confidence: 96%

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Cellular consequences of small supernumerary marker chromosome derived from chromosome 12: mosaicism in daughter and father

Freitas

Santos

Barbosa

et al. 2022

Braz J Med Biol Res

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Constitutional genomic imbalances are known to cause malformations, disabilities, neurodevelopmental delay, and dysmorphia and can lead to dysfunctions in the cell cycle. In extremely rare genetic conditions such as small supernumerary marker chromosomes (sSMC), it is important to understand the cellular consequences of this extra marker, as well the factors that contribute to their maintenance or elimination through successive cell cycles and phenotypic impact. The study of chromosomal mosaicism provides a natural model to characterize the effect of aneuploidy on genome stability and compare cells with the same genetic background and environment exposure, but differing in the presence of sSMC. Here, we report the functional characterization of different cell lines from two familial patients with mosaic sSMC derived from chromosome 12. We performed studies of proliferation dynamics, stability, and variability of these cells using fluorescent in situ hybridization (FISH), sister chromatid exchanges (SCE), and conventional staining. We also quantified the telomere-related genomic instability of sSMC cells using 3D telomeric profile analysis by quantitative-FISH. sSMC cells exhibited differences in the cell cycle dynamics compared to normal cells. First, the sSMC cells exhibited lower proliferation index and higher frequency of SCE than normal cells, associated with a higher level of chromosomal instability. Second, sSMC cells exhibited more telomeric-related genomic instability. Lastly, the differences of sSMC cells distribution among tissues could explain different phenotypic repercussions observed in patients. These results will help in our understanding of the sSMC stability, maintenance during cell cycle, and the cell cycle variables involved in the different phenotypic manifestations.

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Section: Discussionmentioning

confidence: 96%

“…At a cellular level, genomic imbalances such as aneuploidy and microsatellite instability (MSI), and changes in chromosome structure (duplication, deletion, and translocation) are markers of genomic or chromosomal instability (CIN) ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Cellular consequences of small supernumerary marker chromosome derived from chromosome 12: mosaicism in daughter and father

Freitas

Santos

Barbosa

et al. 2022

Braz J Med Biol Res

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“…Specific telomere profiles are associated with disease stability vs. progression [ 18 , 21 , 22 , 23 , 24 , 25 ]. Critically short telomeres, telomere dysfunction, and fusions have all been correlated with disease progression [ 18 , 25 , 27 , 28 , 29 ]. Therefore, telomere profiling may represent both a clinically useful prognostic tool and a potential guide for therapeutic intervention [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Telomere Architecture Correlates with Aggressiveness in Multiple Myeloma

Rangel‐Pozzo

Lal

et al. 2021

Cancers

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The prognosis of multiple myeloma (MM), an incurable B-cell malignancy, has significantly improved through the introduction of novel therapeutic modalities. Myeloma prognosis is essentially determined by cytogenetics, both at diagnosis and at disease progression. However, for a large cohort of patients, cytogenetic analysis is not always available. In addition, myeloma patients with favorable cytogenetics can display an aggressive clinical course. Therefore, it is necessary to develop additional prognostic and predictive markers for this disease to allow for patient risk stratification and personalized clinical decision-making. Genomic instability is a prominent characteristic in MM, and we have previously shown that the three-dimensional (3D) nuclear organization of telomeres is a marker of both genomic instability and genetic heterogeneity in myeloma. In this study, we compared in a longitudinal prospective study blindly the 3D telomeric profiles from bone marrow samples of 214 initially treatment-naïve patients with either monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or MM, with a minimum follow-up of 5 years. Here, we report distinctive 3D telomeric profiles correlating with disease aggressiveness and patient response to treatment in MM patients, and also distinctive 3D telomeric profiles for disease progression in smoldering multiple myeloma patients. In particular, lower average intensity (telomere length, below 13,500 arbitrary units) and increased number of telomere aggregates are associated with shorter survival and could be used as a prognostic factor to identify high-risk SMM and MM patients.

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“…Other factors, including increased glucose uptake, angiogenesis, an altered tumor microenvironment (TME) and a cell's ability to avoid immune surveillance via masking of checkpoint inhibitors such as PD-L1, may allow invasion of these genetically and phenotypically abnormal cells into the blood stream where they present as circulating tumor or CTCs. One of the hallmarks of CTCs is genetic heterogeneity and genomic or chromosomal instability (CIN) [33]. CIN includes microsatellite instability (MSI), chromosome structural variations such as deletions, duplications and translocations, as well as chromosome number.…”

Section: Pathogenesis Of Ctcsmentioning

confidence: 99%

“…Aneuploidy, due to errors in chromosomal segregation, is a consequence of CIN and is implicated in tumorigenesis as evidenced by the increased rate of malignancies found in patients with global or mosaic aneuploidies. The knowledge that aneuploidy is a sine qua non or essential element of a malignant cell forms the basis of certain LB tests that rely on the demonstration of aneuploidy to detect CTCs or CACs (cytogenetically abnormal cells [24,25,33,34]. Genetic mutations arising in CTCs can be characterized by polymerase chain reaction (PCR) or next generation sequencing (NGS) on a single cell basis as well as by fluorescencein-situ-hybridization (FISH) and immunohistochemistry.…”

Section: Pathogenesis Of Ctcsmentioning

confidence: 99%

Diagnosis of Non-Small Cell Lung Cancer via Liquid Biopsy Highlighting a Fluorescence-in-situ-Hybridization Circulating Tumor Cell Approach

Ye¹,

Xiao²,

Carbone³

et al. 2021

Pathology - From Classics to Innovations

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Lung cancer (LC), is the most common and lethal cancer worldwide. It affects both sexes and in its early stages is clinically silent, until it reaches a more advanced stage, when it becomes highly incurable. In order to improve the high mortality associated with LC there has been an urgent need for screening high risk patients by low dose CT scan (LDCT) for the early detection of small resectable malignant tumors. However, while highly sensitive to detect small lung nodules, LDCT is non-specific, resulting in a compelling need for a complementary diagnostic tool. For example, a non-invasive blood test or liquid biopsy, (LB), could prove quite useful to confirm a diagnosis of malignancy prior to definitive therapy. With the advent of LB becoming increasingly clinically accepted in the diagnosis and management of LC, there has been an explosion of publications highlighting new technologies for the isolation of and detection of circulating tumor cells (CTCs) and cell free tumor DNA (cfDNA). The enormous potential for LB to play an important role in the diagnosis and management of LC to obtain valuable diagnostic information via an approach that may yield equivalent information to a surgical biopsy, regarding the presence of cancer and its molecular landscape is described.

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Genomic Instability in Circulating Tumor Cells

Cited by 11 publications

References 151 publications

Cellular consequences of small supernumerary marker chromosome derived from chromosome 12: mosaicism in daughter and father

Cellular consequences of small supernumerary marker chromosome derived from chromosome 12: mosaicism in daughter and father

Telomere Architecture Correlates with Aggressiveness in Multiple Myeloma

Diagnosis of Non-Small Cell Lung Cancer via Liquid Biopsy Highlighting a Fluorescence-in-situ-Hybridization Circulating Tumor Cell Approach

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