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Dihydropyrimidine Dehydrogenase Deficiency and Fluoropyrimidine-Toxicity
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
André B. P. van Kuilenburga, Eva Gross
Previously, it has been suggested that DPYD might be prone to high recombination rates due to the common fragile site FRA1E which extends over 370 kb within the DPYD locus [39]. Common fragile sites represent chromosome structures that are particularly prone to breakage under replication stress and the genomic instability can give rise to deletions, translocations and amplifications. Following the detection of such DPYD rearrangements in pediatric patients with a profound DPD deficiency [40], evidence for a large genomic deletion within DPYD was further obtained in a breast cancer patient who presented with grade 4–5FU toxicity and reduced DPD activity [22]. The deleted region, encompassing exons 21–23, was located in proximity to the common fragile site FRA1E. The patient suffered from severe leukopenia and febrile neutropenia which led to interruption of the chemotherapy and in the course to the development of brain metastases (unpublished results). Subsequently, two additional patients have been identified, suffering from severe fluoropyrimidine associated toxicity, with a genomic amplification of exons 9–12 and 17–18 of DPYD [33, 41]. The fact that several studies did not observe large intragenic aberrations within DPYD in patients suffering from high-grade 5FU toxicity [42–44] suggests a minor role of this mechanism in the susceptibility for 5FU toxicity. However, it should be considered in severe cases of fluoropyrimidine intolerance when conventional PCR-based methods do not reveal any mutations.
The laboratory basis of medical genetics
Published in Peter S. Harper, The Evolution of Medical Genetics, 2019
A third area which would link cytogenetics with clinical molecular genetics at both service and research levels was the study of fragile sites, in particular fragile X syndrome. This condition had long been recognised clinically, first in 1943, by J Purdon Martin and Julia Bell, as a specific X-linked disorder causing mental handicap and some other distinctive features, but in 1969 Herbert Lubs, at that time in America, noted the association with apparent fragility of the terminal part of the long arm of the X chromosome. Initially searches for this in other patients with X-linked mental handicap proved negative, but after it was realised by Grant Sutherland [60] and others (Sutherland and Ashforth 1979) that the fragile site was only visible if specific culture media were used, it became clear that it was considerably commoner than thought originally to be the case, and that the inheritance pattern was unusual, with transmission through clinically normal males, not to be expected from an X-linked disorder. As molecular gene mapping and isolation advanced, a major international initiative developed, in part collaborative, in part competitive, which included several UK members including the laboratories of Kay Davies and Patricia Jacobs, while the original suggestion of a two-step process including a premutation, to explain the anomalous inheritance, came from Marcus Pembrey and Robin Winter in London (Pembrey et al. 1985). The final recognition of DNA instability as the underlying mechanism in this and a series of other disorders is described in the next chapter.
Chromosome abnormalities
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Fragile sites occur on several chromosomes, giving the appearance of breakage at a specific point. On the autosomes they are entirely harmless, being seen usually only in the heterozygous state. On the X chromosome, the occurrence of a fragile site near the end of the long arm (at Xq27.3) is generally associated in males with the important form of X-linked mental retardation, the fragile X syndrome. This is discussed in more detail in Chapter 15. Note that there are two other X-chromosome fragile sites (FRAXE and FRAXF) close to the FRAXA site at Xq27.3. FRAXE has much less association with cognitive impairment, and the FRAXF site may be without any phenotypic association.
Diagnostic significance of miRNAs as potential biomarkers for human renal cell carcinoma: a systematic review and meta-analysis
Published in Expert Review of Anticancer Therapy, 2022
RCC is one of the most common malignant tumors of the urinary system, which is currently primarily detected and diagnosed by imaging technologies. Although the popularity of CT, MRI, FDG-PET, and other techniques make it possible to detect early and smaller kidney cancer, the early diagnosis rate is still low. Although some long non-coding RNAs (lncRNAs) and DNA methylation biomarkers are helpful in the diagnosis of RCC, they lack sensitivity and specificity [33,34]. Therefore, it is necessary to further explore new biomarkers for early detection of renal cancer, which is also of great significance for renal cancer treatment, monitoring of recurrence, and prognosis prediction. At present, ~2,588 miRNAs have been found, which are involved in many important cellular biological processes such as cell growth, proliferation, migration, and apoptosis. Most of them are located in tumor-related fragile sites or gene regions, which are closely related to the occurrence and development of tumors [35].
Beyond visualization of DNA double-strand breaks after radiation exposure
Published in International Journal of Radiation Biology, 2022
I researched two major themes in the Bonner lab. One was to clarify the correlation between DNA damage and cellular senescence. Although it had already been reported that DNA damage accumulates during both cellular senescence and organismal aging (D'Adda di Fagagna et al. 2003; Herbig et al. 2004; Sedelnikova et al. 2004), the origin of DNA damage had not been clarified. Therefore, I established a method to directly establish the relationship between DNA damage and cellular senescence. The method I chose was a combination of γ-H2AX and telomere FISH. However, to achieve simultaneous staining of γ-H2AX and telomere FISH, it is important to maintain both γ-H2AX and DNA information to observe both signals on the same slide under a microscope, and this had not previously been established. After several months of trial and error, I succeeded in establishing the γ-H2AX-FISH method (Nakamura et al. 2006; Nakamura 2013). By using this technique, it was possible to clarify where in the genome the DNA DSB associated during cellular senescence, and I demonstrated that the origin of the DNA damage that accumulates with aging differs depending on the species (Nakamura et al. 2008). Since this technique can visualize the presence of DSB at a specific site in the genome by using a specific DNA probe, it is possible to clearly show whether DNA damage is really induced in Fragile sites existing in the human genome (Kumari et al. 2009).
Targeting translesion synthesis (TLS) to expose replication gaps, a unique cancer vulnerability
Published in Expert Opinion on Therapeutic Targets, 2021
Sumeet Nayak, Jennifer A. Calvo, Sharon B. Cantor
DNA replication is fundamental to the propagation of all life forms and its integrity is critical for heredity and genome stability [1,2]. Accordingly, dysregulated replication invariably generates DNA mutations and/or chromosomal instability. Moreover, defects in replication proficiency are associated with premature aging and cancer [3,4]. To maintain genome integrity, DNA replication employs a dynamic process that readily responds to a range of DNA perturbations, generally described as replication stress (RS) [5]. RS derives from endogenous metabolic byproducts such as aldehydes, oxygen and nitrogen free radicals that modify DNA bases, or from environmental sources such as ultraviolet (UV) light or chemotherapies that modify DNA structure with adducts or crosslinks which, if left unrepaired, leads to DNA damage [5]. DNA replication is also challenged by insufficient building blocks, which occurs by depletion of nucleotides, for example,when cells are treated with the ribonucleotide reductase inhibitor, hydroxyurea (HU) or when cells are prematurely driven into S phase [6,7]. Additional sources of stress include DNA secondary structures that impede DNA replication, such as G-quadruplexes (G4), common fragile sites (CFS) or loop formations occurring in highly repetitive sequences such as microsatellites [8–12].