Advancing Risk Assessment of Intermediate Risk Prostate Cancer Patients

et al. 2020

Cancers

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Circulating tumor cells (CTCs) can promote distant metastases and can be obtained through minimally invasive liquid biopsy for clinical assessment in cancer patients. Having both genomic heterogeneity and instability as common features, the genetic characterization of CTCs can serve as a powerful tool for a better understanding of the molecular changes occurring at tumor initiation and during tumor progression/metastasis. In this review, we will highlight recent advances in the detection and quantification of tumor cell heterogeneity and genomic instability in CTCs. We will focus on the contribution of chromosome instability studies to genetic heterogeneity in CTCs at the single-CTC level by discussing data from different cancer subtypes and their impact on diagnosis and precision medicine.

Section: Genetic and Chromosome Instabilitymentioning

confidence: 99%

Genomic Instability in Circulating Tumor Cells

Freitas

Gartner

et al. 2020

Cancers

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“…In light of the expanding spectrum of p53 anti-tumor activity, it is essential to investigate the relation of p53 to other components of cancer. Changes in nuclear architecture are a key hallmark of cancer [26][27][28][29][30][31][32][33]. The three-dimensional (3D) nuclear organization can be described by the 3D organization of chromosomes, where chromosomes occupy specific nuclear areas organized into discrete chromosome territories, with DNA interactions across boundaries infrequent [34][35][36].…”

Section: Introductionmentioning

confidence: 99%

“…3D telomere signatures are a useful method for studying architectural changes in the nucleus of malignant and non-transformed cells [27][28][29][30]. Telomeres consist of (TTAGGG) n repeats that are present at the ends of all eukaryotic chromosomes and form unique nucleoprotein complexes [46].…”

Section: Introductionmentioning

confidence: 99%

“…It has been demonstrated that normal lymphocytes telomeres are organized in a non-overlapping manner and their localization during the cell cycle is tightly regulated [48]. Dysregulation in the normal distribution of telomeres is an early event in tumorigenesis [27][28][29][30]. Quantitative 3D telomere fluorescence in-situ hybridization (3D Q-FISH) has previously been used to characterize telomere dysfunction, changes in the nuclear organization and genomic instability [27][28][29][30][40][41][42][43][44][45].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, 3D imaging and quantitative 3D analysis of telomeres can provide additional information about the global nuclear architecture of cells. Additionally, 3D telomere profiling has been shown to be successful in stratifying patients and predicting response to therapy [28]. The analysis of more than 3000 tumors had shown that p53 mutations are strongly correlated with a high genomic instability [51][52][53].…”

Section: Introductionmentioning

confidence: 99%

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p53 CRISPR Deletion Affects DNA Structure and Nuclear Architecture

Booth

et al. 2020

JCM

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The TP53 gene is a key tumor suppressor. Although the tumor suppressor p53 was one of the first to be characterized as a transcription factor, with its main function potentiated by its interaction with DNA, there are still many unresolved questions about its mechanism of action. Here, we demonstrate a novel role for p53 in the maintenance of nuclear architecture of cells. Using three-dimensional (3D) imaging and spectral karyotyping, as well as super resolution microscopy of DNA structure, we observe significant differences in 3D telomere signatures, DNA structure and DNA-poor spaces as well gains or losses of chromosomes, between normal and tumor cells with CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-deleted or wild-type TP53. Additionally, treatment with Nutlin-3 results in differences in nuclear architecture of telomeres in wild-type but not in p53 knockout MCF-7 (Michigan Cancer Foundation-7) cells. Nutlin-3 binds to the p53-binding pocket of mouse double minute 2 (MDM2) and blocks the p53-MDM2 interaction. Moreover, we demonstrate that another p53 stabilizing small molecule, RITA (reactivation of p53 and induction of tumor cell apoptosis), also induces changes in 3D DNA structure, apparently in a p53 independent manner. These results implicate p53 activity in regulating nuclear organization and, additionally, highlight the divergent effects of the p53 targeting compounds Nutlin-3 and RITA.

Three‐dimensional nuclear architecture distinguishes thyroid cancer histotypes

Santos

Dettori

et al. 2023

Intl Journal of Cancer

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Molecular markers can serve as diagnostic tools to support pathological analysis in thyroid neoplasms. However, because the same markers can be observed in some benign thyroid lesions, additional approaches are necessary to differentiate thyroid tumor subtypes, prevent overtreatment and tailor specific clinical management. This applies particularly to the recently described variant of thyroid cancer referred to as noninvasive follicular thyroid neoplasm with papillary‐like nuclear features (NIFTP). This variant has an estimated prevalence of 4.4% to 9.1% of all papillary thyroid carcinomas worldwide. We studied 60 thyroid lesions: 20 classical papillary thyroid carcinoma (CPTC), 20 follicular variant of PTC (FVPTC) and 20 NIFTP. We examined morphological and molecular features to identify parameters that can differentiate NIFTP from the other PTC subtypes. When blindly investigating the nuclear architecture of thyroid neoplasms, we observed that NIFTP has significantly longer telomeres than CPTC and FVPTC. Super‐resolved 3D‐structured illumination microscopy demonstrated that NIFTP is heterogeneous and that its nuclei contain more densely packed DNA and smaller interchromatin spaces than CPTC and FVPTC, a pattern that resembles normal thyroid tissue. These data are consistent with the observed indolent biological behavior and favorable prognosis associated with NIFTP, which lacks BRAFV600E mutations. Of note, next‐generation thyroid oncopanel sequencing was unable to distinguish the thyroid cancer histotypes in our study cohort. In summary, our data suggest that 3D nuclear architecture can be a powerful analytical tool to diagnose and guide clinical management of NIFTP.