Long telomeres and cancer risk: the price of cellular immortality

McNally, E.; Luncsford, Paz J.; Armanios, Mary

doi:10.1172/jci120851

Cited by 125 publications

(137 citation statements)

References 99 publications

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“…As indicated by the aberration index, groups of patients with lower or higher total CA frequencies were not observed (Fig 8E, Supp Fig 4C). These results in conjunction with the telomere length data, identified two patients (ID #s 6, 16) at potentially increased risks for secondary cancers [14][15][16]47 , and are supportive of inversions and deletions being more informative than other CA types for predicting IR-induced secondary cancers, consistent with prior reports 55 . These results also indicate that the numbers of cells scored were too low (n=30) to detect significant differences in individual patient susceptibility to chromosomal instability in general.…”

Section: Longitudinal Analyses Of Chromosomal Instability Associatedsupporting

confidence: 85%

“…When clustering patients by CA type, we observed groups of patients with differential responses only for inversions and chromosome fragments (deletions), which displayed increased frequencies immediately post-IMRT, suggesting increased chromosomal instability (Fig 8A/D, Supp Fig 3A/B). We note that the two patients with the highest post-IMRT frequencies of inversions (ID #16) and chromosome fragments (ID #6), also had very high post-IMRT MTLs; both biomarkers suggestive of increased risks for secondary cancers [14][15][16]47 (Fig 1C, Fig 8A/D, Supp Fig 3A/B).…”

Section: Longitudinal Analyses Of Chromosomal Instability Associatedmentioning

confidence: 88%

“…Predicting a patient's telomeric response to radiation therapy is of clinical interest for predicting risks of radiation late effects, as shorter telomeres confer radiosensitivity 34 and increase risk of degenerative late effects (CVD 42 , pulmonary fibrosis 42 , aplastic anemia 43 ), while longer telomeres increase risk for secondary cancers, particularly leukemias 47 . Given that telomeric responses to radiation exposure can be highly dynamic [35][36][37][38][39][40] and vary between individuals (Fig 1-3), a framework for predicting a patient's particular telomeric responses to radiation therapy is critical for utilizing telomere length as a biomarker for radiation late effects.…”

Section: Discussionmentioning

confidence: 99%

“…Those patients that clustered in group 2 (n=11) had relatively shorter MTL at baseline, and showed a dramatic, sustained increase in MTL post-IMRT (Fig 1C). Reduced MTL three months post-IMRT suggests increased risks for degenerative radiation late effects 42,43 , while increased MTL suggests increased risks for proliferative secondary cancers 47 .…”

Section: Telomere Length Dynamics Revealed Individual Differences Inmentioning

confidence: 99%

“…Short telomeres are biomarkers and even effectors for a range of aging-related pathologies 41 , including cardiovascular disease (CVD) 42 , pulmonary fibrosis 42 , and aplastic anemia 43 , degenerative conditions also regarded as radiation late effects [44][45][46] . On the other hand, longer telomeres are associated with increased cancer risk, particularly for leukemias 47 , a common cancer following IR-exposure 48 . Thus, patients with shorter telomeres after radiation therapy are more likely to develop short telomere (degenerative) pathologies, while patients with longer telomeres following radiotherapy are at higher risk for developing proliferative pathologies (cancer).…”

Section: Introductionmentioning

confidence: 99%

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Telomere length and chromosomal instability for predicting individual radiosensitivity and risk via machine learning

Luxton

McKenna

Lewis

et al. 2020

Preprint

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The ability to predict responses of cancer patients to radiotherapy and risks of developing adverse late health effects would greatly improve personalized treatment regimens and individual outcomes. Telomeres represent a compelling biomarker of individual radiosensitivity and risk, as exposure can result in dysfunctional telomere pathologies that coincidentally overlap with many radiation-induced late effects, ranging from degenerative conditions like fibrosis and cardiovascular disease to proliferative pathologies like cancer. Here, telomere length was longitudinally assessed in a cohort of fifteen prostate cancer patients undergoing Intensity Modulated Radiation Therapy (IMRT) utilizing Telomere Fluorescence in situ Hybridization (Telo-FISH). To evaluate genome instability and enhance predictions for individual patient risk of secondary malignancy, chromosome aberrations were also assessed utilizing directional Genomic Hybridization (dGH) for high-resolution inversion detection. We present the first implementation of individual telomere length data in a machine learning model, XGBoost, trained on pre-radiotherapy (baseline) and in vitro exposed (4 Gy γ-rays) telomere length measures, to predict post-radiotherapy telomeric outcomes, which together with chromosomal instability provide insight into individual radiosensitivity and risk for radiation-induced late effects.2 Introduction:

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Section: Longitudinal Analyses Of Chromosomal Instability Associatedsupporting

confidence: 85%

Section: Longitudinal Analyses Of Chromosomal Instability Associatedmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Telomere Length Dynamics Revealed Individual Differences Inmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Telomere length and chromosomal instability for predicting individual radiosensitivity and risk via machine learning

Luxton

McKenna

Lewis

et al. 2020

Preprint

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Regulator of telomere elongation helicase 1 gene and its association with malignancy

2022

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Background With the progression of next‐generation sequencing technologies, researchers have identified numerous variants of the regulator of telomere elongation helicase 1 ( RTEL1 ) gene that are associated with a broad spectrum of phenotypic manifestations, including malignancies. At the molecular level, RTEL1 is involved in the regulation of the repair, replication, and transcription of deoxyribonucleic acid (DNA) and the maintenance of telomere length. RTEL1 can act both as a promotor and inhibitor of tumorigenesis. Here, we review the potential mechanisms implicated in the malignant transformation of tissues under conditions of RTEL1 deficiency or its aberrant overexpression. Recent findings A major hemostatic challenge during RTEL1 dysfunction could arise from its unbalanced activity for unwinding guanine‐rich quadruplex DNA (G4‐DNA) structures. In contrast, RTEL1 deficiency leads to alterations in telomeric and genome‐wide DNA maintenance mechanisms, ribonucleoprotein metabolism, and the creation of an inflammatory and immune‐deficient microenvironment, all promoting malignancy. Additionally, we hypothesize that functionally similar molecules could act to compensate for the deteriorated functions of RTEL1 , thereby facilitating the survival of malignant cells. On the contrary, RTEL1 over‐expression was directed toward G4‐unwinding, by promoting replication fork progression and maintaining intact telomeres, may facilitate malignant transformation and proliferation of various pre‐malignant cellular compartments. Conclusions Therefore, restoring the equilibrium of RTEL1 functions could serve as a therapeutic approach for preventing and treating malignancies.

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Integrated metabolic and genetic analysis reveals distinct features of human differentiated thyroid cancer

Cararo-Lopes

Sawant

Moore

et al. 2023

Clinical & Translational Med

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Background: Differentiated thyroid cancer (DTC) affects thousands of lives worldwide each year. Typically, DTC is a treatable disease with a good prognosis. Yet, some patients are subjected to partial or total thyroidectomy and radioiodine therapy to prevent local disease recurrence and metastasis. Unfortunately, thyroidectomy and/or radioiodine therapy often worsen(s) quality of life and might be unnecessary in indolent DTC cases. On the other hand, the lack of biomarkers indicating a potential metastatic thyroid cancer imposes an additional challenge to managing and treating patients with this disease. Aim: The presented clinical setting highlights the unmet need for a precise molecular diagnosis of DTC and potential metastatic disease, which should dictate appropriate therapy. Materials and methods:In this article, we present a differential multi-omics model approach, including metabolomics, genomics, and bioinformatic models, to distinguish normal glands from thyroid tumours. Additionally, we areThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Long telomeres and cancer risk: the price of cellular immortality

Cited by 125 publications

References 99 publications

Telomere length and chromosomal instability for predicting individual radiosensitivity and risk via machine learning

Telomere length and chromosomal instability for predicting individual radiosensitivity and risk via machine learning

Regulator of telomere elongation helicase 1 gene and its association with malignancy

Integrated metabolic and genetic analysis reveals distinct features of human differentiated thyroid cancer

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