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High-grade Glioma
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Donald C. Macarthur, Christof M. Kramm, Matthias A. Karajannis
In addition to histones, other chromatin regulators have been found to be mutated in pediatric HGG. The ATRX or DAXX genes, which are associated with a telomerase-independent process called alternative lengthening of telomeres (ALT), are mutated in approximately 20% of pediatric HGG, often with concurrent G34 mutations.10,23 In contrast, mutations of the telomerase reverse transcriptase (TERT) promoter, which represents a different mechanism of telomere lengthening commonly seen in adult glioblastoma, are very rare in the pediatric population.26
Preventing Premature Cell Cycling
Published in Robert Fried, Lynn Nezin, Evidence-Based Proactive Nutrition to Slow Cellular Aging, 2017
SIRT1 may also influence a second maintenance pathway called “alternative lengthening of telomeres” (ALT): SIRT1 over production promoted chromosome end DNA repair. Conversely, SIRT1-deficient cells showed increased damage at their chromosome ends. SIRT1 therefore maintained telomere length and integrity, which may explain why SIRT1-overexpressing mice stay healthier for longer (Short 2010).
Neuroendocrine tumors of the gastrointestinal tract
Published in Demetrius Pertsemlidis, William B. Inabnet III, Michel Gagner, Endocrine Surgery, 2017
Bernard Khoo, Tricia Tan, Stephen R. Bloom
Mutations in menin therefore appear to cause the dysregulation of multiple cellular pathways, but the ultimate pathogenic links between menin and pancreatic NET tumorigenesis are still obscure. The key importance of menin in the pathogenesis of sporadic pancreatic NETs is reinforced by studies that show that 44% of 68 pancreatic NETs samples were shown to have mutations in MEN1, as opposed to none of the pancreatic adenocarcinoma samples. The same study showed that other key pathways were mutated in sporadic pancreatic NETs. DAXX (death-domain associated protein) and ATRX (alpha-thalassemia/mental retardation syndrome X-linked) mutations have been found to occur, collectively, in 43% of pancreatic NETs and none of pancreatic adenocarcinomas [8]. Mutations in both DAXX and ATRX appear to activate the so-called “alternative lengthening of telomeres” (ALT) pathway, which would be expected to immortalize cells. Indeed, 61% of sporadic pancreatic NETs show signs of ALT activity [9]. Notably, patients with pancreatic NETs that possessed mutations in MEN1, DAXX, or ATRX had prolonged survival compared with those patients whose pancreatic NETs did not possess these mutations. MEN1, DAXX, and ATRX mutations may therefore specify a class of pancreatic NETs with a relatively good prognosis; however, the robustness of this concept is yet to be tested prospectively.
Ad Astra – telomeres in space!
Published in International Journal of Radiation Biology, 2022
Susan M. Bailey, Jared J. Luxton, Miles J. McKenna, Lynn E. Taylor, Kerry A. George, Sameer G. Jhavar, Gregory P. Swanson
Telomeres – literally the “end-part” of linear chromosomes – are composed of tandem arrays of highly conserved repetitive G-rich sequence (5′-TTAGGG-3′ in humans) bound by an assortment of telomere-specific and nonspecific proteins that protect chromosomal termini from degradation and loss (Muller 1938; Moyzis et al. 1988; de Lange 2005). Telomeres also preserve genome stability by preventing the natural ends of chromosomes from being recognized as broken DNA (double-strand breaks; DSBs), and thereby avoiding inappropriate DDRs. It has long been recognized that due to the end-replication problem (inability of conventional polymerases to replicate to the very end of linear DNA), telomere length shortens with cell division (Olovnikov 1971; Watson 1972). Telomerase is the specialized reverse transcriptase capable of counteracting telomere attrition via de novo addition of telomeric repeats onto the ends of newly synthesized chromosomes (Greider and Blackburn 1985). However, telomerase activity is repressed in most somatic tissues, being sufficient to maintain telomere length only in highly proliferative stem, germline, and the vast majority of cancer cells (Kim et al. 1994; Yuan et al. 2019). The remaining ∼10 to15% of cancers maintain telomere length via the telomerase independent, recombination-based Alternative Lengthening of Telomeres (ALT) pathway of telomere maintenance (Murnane et al. 1994; Bryan et al. 1997; Dunham et al. 2000).
State-of-the-art, approved therapeutics for the pharmacological management of osteosarcoma
Published in Expert Opinion on Pharmacotherapy, 2021
Cristina Meazza, Sebastian Dorin Asaftei
OS is a genetically unstable malignancy, associated with many somatic structural variations (SV) and copy number alterations. It carries complex genotypes, with a median of approximately 1.2 mutations/megabase – as opposed to the 0.1 mutations/megabase reported in most other pediatric tumors. About one in three samples of OS reveal chromosomal alterations in the form of chromothripsis, i.e. single catastrophic events that give rise to genomic instability, and leading to hundreds of genomic rearrangements. This is a feature of just 2–3% of all cancers. OS also reveals patterns of kataegis (localized hypermutations) in 50–85% of cases. The genomic instability of OS is also exacerbated by alternative lengthening of telomeres (ALT), a homologous recombination-dependent mechanism that prevents telomere shortening and causes senescence.
What is the best clinical approach to recurrent/refractory osteosarcoma?
Published in Expert Review of Anticancer Therapy, 2020
Cristina Meazza, Stefano Bastoni, Paolo Scanagatta
So far, whole-genome and next-generation sequencing approaches have confirmed the genomic complexity of OS [106] and its inter- and intratumoral heterogeneity [107]: unfortunately none of the discoveries have led to the development of molecularly targeted therapies capable of improving patient survival. OS is characterized by chromosomal instability, and high levels of somatic structural variations (SV), and copy number alterations. Approximately 33% of OS samples show signs of chromothripsis (a single catastrophic event causing genomic instability, resulting in hundreds of genomic rearrangements), as opposed to 2–3% of cancers as a whole; and 50–85% of all OSs exhibit patterns of localized hypermutation known as kataegis. Moreover, OSs show an alternative lengthening of telomeres (ALT), a homologous recombination-dependent mechanism that prevents telomere shortening and induces senescence: longer telomeres are associated with poor clinical outcomes. So it is clear that different structural and numerical aberrations have very different biological effects, and large-scale studies will be needed to accumulate enough biological data to shed light on the matter [108].