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Werner Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The localization by linkage study of the culprit gene region to chromosome 8 in 1992 and the identification by positional cloning of the WRN gene in 1996 revealed molecular insights on the pathogenesis of Werner syndrome. Indeed, these new findings helped clarify the premature aging seen in Werner syndrome as distinct from normal aging on a cellular level [3–5]. Further, the characterization of the WRN encoded product as RecQ helicase (RECQL2), one of five members (i.e., RECQL1, BLM, WRN, RECQL4, and RECQL5) in the RecQ helicase family, helped link Werner syndrome to Bloom syndrome (BLM) and Rothmund−Thomson syndrome (RECQL4), each of which features genomic instability and susceptibility to cancer, and each of which demonstrates notable differences in the characteristics of genomic instability and the sites and types of cancers associated [6,7].
Nodular Thyroid Disease with Aging
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Enke Baldini, Salvatore Sorrenti, Antonio Catania, Francesco Tartaglia, Daniele Pironi, Massimo Vergine, Massimo Monti, Angelo Filippini, Salvatore Ulisse
DTC is generally sporadic. Familial forms are responsible for 3%–6% of cases, and are observed in familial syndromes including: (i) familial adenomatous polyposis, characterized by mutations in the APC (adenomatosis polyposis coli) gene; (ii) Cowden disease, characterized by mutations in the PTEN (phosphatase and tensin homolog) gene; (iii) Werner syndrome, associated with mutations in the WRN (Werner syndrome, RecQ helicase-like) gene; (iv) Carney complex, showing mutations in the PRKAR1A (protein kinase, cAMP-dependent, regulatory subunit type I alpha) gene. In addition, susceptibility gene loci have been identified in other familial syndromes in which PTC is associated with papillary renal carcinomas (1q21), clear-cell renal-cell carcinoma (p14.2;q24.1) [3,10], and multinodular goiter (19p13.2) [10,22,23].
Genomic Instability During Aging of Postmitotic Mammalian Cells
Published in Alvaro Macieira-Coelho, Molecular Basis of Aging, 2017
Since chromosomal aberrations appear to be associated with normal in vivo aging of nondividing and dividing mammalian cells, it is obvious to look at naturally occurring diseases that exhibit greater instability than normal. Human genetic disorders, such as ataxia telangiectasia and Werner’s syndrome, show increased chromosomal instability.48,97–100 These disorders have certain aspects that might be interpreted as evidence for the premature onset of senescence or accelerated aging processes, and are therefore referred to as segmental progeroid syndromes.99 Segmental progeroid syndromes are defined as those genetic disorders in which multiple major features of the senescent phenotype appear much earlier than clinically normal age-matched subjects.100 A marked increase in the predisposition to cancers is part of the syndrome phenotype. Both disorders are rare autosomal recessive alleles. Werner’s syndrome patients present clinically with a number of geriatric symptoms beginning about the time of puberty and culminating at death with a median age of 47 years.99 The replicative life span of cultured Werner’s syndrome cells is significantly less than controls.101 Cytogenetic analysis of cultured somatic cells from patients with Werner’s syndrome have revealed a high frequency of translocations, deletions, and inversions.102–105 This instability was also observed at the level of the gene. Spontaneous mutations in the hypoxanthine-guanine phosphoribosyl transferase (HPRT) gene, mostly relatively large deletions, were eightfold higher than those of control subjects.106 These observations have been interpreted as a coupling of chromosomal instability, cancer, and aging.48
Ewing sarcoma: investigational mono- and combination therapies in clinical trials
Published in Expert Opinion on Investigational Drugs, 2021
Jessica Gartrell, Carlos Rodriguez-Galindo
Another compound that has shown potential in disrupting the fusion is trabectedin. It has long been known that trabectedin can disrupt crucial downstream targets of EWS-FLI1; however, its clinical use has been limited by its narrow therapeutic range [23]. Therefore, there has been growing attention to look for synergistic combinations that may improve on tolerability and increase the therapeutic window. Grohar et al. [23] showed through siRNA experiments that the EWS-FLI1 fusion increases the expression of the Werner syndrome protein (WRN) in ES cell lines. This protein was previously described to be deficient in patients who have Werner syndrome, a premature aging and cancer predisposition syndrome marked by DNA repair defects [23]. This finding led the investigators to hypothesize that the combination of the topoisomerase I inhibitor, SN-38 [active metabolite of irinotecan (IRN)] and trabectedin may be synergistic (as cells deficient in the Werner syndrome protein are sensitive to camptothecins). Indeed, the combination was active both in vivo and in vitro, with increased markers of damage and significant tumor regression in xenograft models. Harlow et al. [24] elucidated a potential mechanism of action of trabectedin by showing that treatment with trabectedin redistributes the fusion from the nucleus to nucleolus, resulting in loss of the ability of the SWI/SNF complex to bind to chromatin. This complex is required for EWS-FLI1’s function as a transcription factor. While promising, they showed that it requires a high number of compounds to achieve these effects. To combat this, the authors were able to show that treatment with a low dose of IRN could increase the ability of trabectedin to suppress EWS-FLI1 targets, leading to tumor regression in preclinical models. Herzog et al. [25] reported a series of 12 patients with various fusion-positive sarcomas, including eight with ES, who were given trabectedin and IRN on variable schedules as part of a compassionate use program. In a retrospective review, four out of eight patients with ES experienced prolonged stable disease, with one patient receiving 11 cycles. A prospective phase I study of the combination is currently being developed (NCT04067115).