Werner Syndrome
Dongyou Liu in 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
Shamim I. Ahmad in Aging: Exploring a Complex Phenomenon, 2017
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].
Intrinsic Biological Aging As Underlying Pathogenetic Mechanisms in Dementias of the Alzheimer’s Type
Zaven S. Khachaturian, Teresa S. Radebaugh in Alzheimer’s Disease, 2019
As indicated above, we human beings are exceptionally heterogeneous from a genetic point of view. With the exception of identical twins (or some futuristic somatic cell cloning), one could state that no two individuals have ever been born or will ever be born who will be genetically identical. What can we learn from a study of how these genetic variations might influence patterns of aging? Such research is still in its infancy. One can tentatively make several important conclusions, however. First, it is clear that there does not exist a single genetic locus’ mutation at which can accelerate all of the known features of aging. This is not surprising, given the above discussion of evolutionary aspects of aging. Second, there are gene mutations with profound and widespread effects upon patterns of aging in multiple organ systems but which appear to spare the central nervous system. A striking example is the Werner syndrome. It is sometimes referred to as “Progeria of the Adult” to distinguish it from “Progeria of Childhood” (the Hutchinson-Gilford syndrome or “Progeria”). The Werner syndrome is inherited as an autosomal recessive, whereas, the Hutchinson-Gilford syndrome is probably inherited as an autosomal dominant. They are likely be due to mutations at different genetic loci. There has been more progress for the case of the Werner syndrome, the mutation for which maps to the short arm of the number 8 chromosome. The responsible gene may code for an enzyme or for a transcription factor. Its deficiency leads to premature greying and thinning of the hair, atrophy of skin, regional atrophy of subcutaneous fat, ocular cataracts, insulin-resistant diabetes mellitus, osteoporosis, hypogonadism, various forms of arteriosclerosis, and various forms of benign and malignant neoplasms. The usual cause of death is a myocardial infarction due to atherosclerosis, and the second most common cause of death is cancer. The median age of death is 47. The patients appear to be normal at birth and during childhood, but fail to undergo the usual adolescent growth spurt. (They thus are quite short as adults.) Although there have been occasional reports of central nervous system pathologies, the great majority of patients age without signs or symptoms of accelerated aging within the brain. Autopsy examinations have failed to document any of the changes found in AD. One does not know if the mechanisms whereby patients with the Werner syndrome develop these various age-related abnormalities are comparable to what is operative in most individuals. The findings do demonstrate, however, an uncoupling of these peripheral types of pathologies from the most common type of age-related pathology in the brain, AD. Similarly, it is the case that there are several different genetic loci in man that can modulate one’s susceptibility to AD, but which appear not to have any significant peripheral effects.
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).
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