Three-dimensional Nuclear Telomere Architecture Is Associated with Differential Time to Progression and Overall Survival in Glioblastoma Patients

Gadji, Macoura; Fortin, David; Tsanaclis, Ana-Maria; Garini, Yuval; Katzir, Nir; Wienburg, Yifat; Yan, Jun; Klewes, Ludger; Klonisch, Thomas; Drouin, Régen; Mai, Sabine

doi:10.1593/neo.91752

Cited by 49 publications

(86 citation statements)

References 31 publications

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“…These telomere changes were absent in heterozygous Thrb PV/ + or control mice. Our findings confirm previous reports identifying 3D telomere FISH as an effective diagnostic tool for early detection of individual cancer cells, tumor subtypes, and suitable prognostic indicator of disease progression (24,25,31,62). Recently, we developed an automated 3D telomere scanning procedure capable of rapid imaging of telomere profiles from interphase nuclei, and specific TeloScan software was shown to identify individual tumor cells in large samples (63).…”

Section: Discussionsupporting

confidence: 88%

“…We previously showed significant differences in telomeric profiles (i.e., in telomere signal intensity and number, the presence/absence of telomeric aggregates, and in the number of telomeres per nuclear volumes) in therapy-sensitive and therapy-resistant Hodgkin's lymphoma patients (24). These results demonstrated the prognostic value of three-dimensional (3D) telomere diagnostic imaging for glioblastoma patients (25), and suggested a 3D telomere dysfunction-based progression model leading to the progression of myelodysplastic syndromes to acute myeloid leukemias (26).…”

Section: Trb1mentioning

confidence: 71%

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Three-Dimensional Telomere Dynamics in Follicular Thyroid Cancer

Wark

Danescu

Natarajan

et al. 2014

Thyroid

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Background: Over the last decade, annual incidence rates for thyroid cancer have been among the highest of all cancers in the Western world. However, the genomic mechanisms impacting thyroid carcinogenesis remain elusive. Methods: We employed an established mouse model of follicular thyroid cancer (FTC) with a homozygous proline to valine mutation (Thrb PV/PV ) in the thyroid receptor b1 (TRb1) and applied quantitative threedimensional (3D) telomere analysis to determine 3D telomeric profiles in Thrb PV/PV , Thrb PV/ + , and Thrbmouse thyrocytes before and after histological presentation of FTC.Results: Using quantitative fluorescent in situ hybridization (Q-FISH) and TeloViewÔ image analysis, we found altered telomeric signatures specifically in mutant mouse thyrocytes. As early as 1 month of age, Thrb PV/PV mouse thyrocytes showed more telomeres than normal and heterozygous age-matched counterparts. Importantly, at the very early age of 1 month, 3D telomeric profiles of Thrb PV/PV thyrocyte nuclei reveal genetic heterogeneity with several nuclei populations exhibiting different telomere numbers, suggestive of various degrees of aneuploidy within the same animal. This was detected exclusively in Thrb PV/PV mice well before the presentation of histological signs of thyroid carcinoma. Conclusions: We identified quantitative 3D telomere analysis as a novel tool for early detection and monitoring of thyrocyte chromosomal (in)stability. This technique has the potential to identify human patients at risk for developing thyroid carcinoma.

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Section: Discussionsupporting

confidence: 88%

Section: Trb1mentioning

confidence: 71%

Three-Dimensional Telomere Dynamics in Follicular Thyroid Cancer

Wark

Danescu

Natarajan

et al. 2014

Thyroid

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“…We anticipate the use of this scanning technology in the detection of rare cancer cells, in the screening of risk groups, and in the assessment of treatment success. Moreover, it has already shown to have the ability of sub-classifying patient subgroups that could not previously be identified (11). We also expect its success in guiding patient treatment decisions based on the recognition of recurrent/aggressive telomere profiles observed at diagnosis (40).…”

Section: Discussionmentioning

confidence: 94%

“…Telomere measurements were performed using TeloView for the manual 3D-acquisition (35,38), TeloScan for the automated 3D-acquisition (11). The integrated intensity of each telomere was calculated based on the linear correlation between telomere length and signal intensity.…”

Section: D Image Analysis For Telomeresmentioning

confidence: 99%

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Novel automated three‐dimensional genome scanning based on the nuclear architecture of telomeres

Klewes

Höbsch

Katzir³

et al. 2010

Cytometry Pt A

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Telomeres, the end of chromosomes, are organized in a nonoverlapping fashion and form microterritories in nuclei of normal cells. Previous studies have shown that normal and tumor cell nuclei differ in their 3D telomeric organization. The differences include a change in the spatial organization of the telomeres, in telomere numbers and sizes and in the presence of telomeric aggregates. Previous attempts to identify the above parameters of 3D telomere organization were semi-automated. Here we describe the automation of 3D scanning for telomere signatures in interphase nuclei based on three-dimensional fluorescent in situ hybridization (3D-FISH) and, for the first time, define its sensitivity in tumor cell detection. The data were acquired with a highthroughput scanning/acquisition system that allows to measure cells and acquire 3D images of nuclei at high resolution with 403 or 603 oil and at a speed of 10,000-15,000 cells h 21 , depending on the cell density on the slides. The automated scanning, TeloScan, is suitable for large series of samples and sample sizes. We define the sensitivity of this automation for tumor cell detection. The data output includes 3D telomere positions, numbers of telomeric aggregates, telomere numbers, and telomere signal intensities. We were able to detect one aberrant cell in 1,000 normal cells. In conclusions, we are able to detect tumor cells based on 3D architectural profiles of the genome. This new tool could, in the future, assist in patient diagnosis, in the detection of minimal residual disease, in the analysis of treatment response and in treatment decisions. '

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Nuclear remodeling of telomeres in chronic myeloid leukemia

Samassékou

Mai

Yan

2013

Genes Chromosomes & Cancer

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Chronic myeloid leukemia (CML) is a hematologic cancer characterized by the proliferation of myeloid cells and the translocation between chromosomes 9 and 22, [t(9;22)(q34.1;q11.2)]. At the chronic phase (CP), CML cells present longer telomeres than at the other clinical phases, display arm-specific maintenance of individual telomere lengths, and are chromosomally stable. We asked whether an alteration of nuclear organization of telomeres, which is associated with genomic instability, occurs in CML cells at the CP. We used fluorescent in situ hybridization of telomeres combined with three-dimensional (3D) quantification to study the nuclear telomeric architecture of CML cells at the CP. We found that cells can exhibit high telomere numbers, different telomere distributions, and alterations in peripheral or central nuclear location of telomeres. Also, we show that CML cells can be categorized in two groups according to the number of their telomere aggregates (TAs). We propose that the presence of high TAs in some samples is associated with the increased genomic instability and could be an indication of the clinical transitional phase. Also, alterations of nuclear organization of telomeres at the CP confirm that nuclear remodeling of telomeres can occur at an early clinical stage of a cancer.

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Three-dimensional Nuclear Telomere Architecture Is Associated with Differential Time to Progression and Overall Survival in Glioblastoma Patients

Cited by 49 publications

References 31 publications

Three-Dimensional Telomere Dynamics in Follicular Thyroid Cancer

Three-Dimensional Telomere Dynamics in Follicular Thyroid Cancer

Novel automated three‐dimensional genome scanning based on the nuclear architecture of telomeres

Nuclear remodeling of telomeres in chronic myeloid leukemia

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