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Genetics of Uterine Leiomyomata
Published in John C. Petrozza, Uterine Fibroids, 2020
C. Scott Gallagher, Cynthia C. Morton
Chromosomal rearrangement is hypothesized to alter gene activity by recombining regions of the genome (Figure 5.1). Breakage and repair may be nonviable in many cases, but, at a low frequency, they can create gene fusions encoding novel chimeric proteins and dysregulate gene expression by introducing foreign regulatory elements or removing native ones. Resolution of chromosomal damage can generate cells with survival or growth advantages and result in benign transformation of a myometrial cell [7,57]. Alternatively, chromosomal instability may mostly be inert, with dysregulated growth resulting from primary mutations elsewhere in the genome [6].
Oncogenes and Cancer
Published in Pimentel Enrique, Oncogenes, 2020
Increased chromosome fragility (chromosome instability) is found in several clinical syndromes associated with increased cancer risk.348 A similar fragility has been found in patients with multiple endocrine neoplasia,349 as well as in patients with sporadic unilaterial retinoblastoma.350 A possible relationship between chromosome fragility and neoplastic diseases may be anticipated if this fragility results in loss or alteration of genome segments involved in the transcriptional control of oncogenes or in deletion of tumor-suppressing genes. In general, it is interesting to look for a possible association of familial chromosome fragility at specific sites, especially those corresponding to proto-oncogene loci, and increased incidence of specific types of cancer segregating with the fragile site(s) in the same families.351
Genomic Instability During Aging of Postmitotic Mammalian Cells
Published in Alvaro Macieira-Coelho, Molecular Basis of Aging, 2017
Chromosomal instability. Chromosomal instability is clearly an aging index for dividing and nondividing cells. Comparing young and old animals, frequencies of aberrations are higher in normally nonprolifera ting cells than in proliferating cells.86–93 Liver cells appear to be a paradigm for nondividing cells. The spontaneous frequency of chromosomal aberration of a normally nonreplicating hepatocyte increases as a function of chronological age.81–87 The results show that lesions accumulate at a fairly constant rate, which is characteristic for a species. The rate of development of chromosomal abnormalities is inversely proportional to an animal’s life span for several mammalian species, suggesting a close relationship to basic aging processes. There are numerous studies that show induction of chromosome aberrations per se do not mimic natural senescence, which is difficult to reconcile with the spontaneous aberration results.4,14,15 Whereas additional experiments comparing more species and more cell types would be interesting, it is doubtful that any additional mechanistic insight would be gained. Experiments using fluorescent-in-situ-hybridization with chromosome- or gene-specific probes to obtain sequence-related information on chromosome aberrations might help in revealing the relevance of these events. Furthermore, an attempt should be made to correlate chromosomal aberrations with histological evidence of cell death or mutations.
Novel and emerging targets for cholangiocarcinoma progression: therapeutic implications
Published in Expert Opinion on Therapeutic Targets, 2022
Lionel A. Kankeu Fonkoua, Pedro Luiz Serrano Uson Junior, Kabir Mody, Amit Mahipal, Mitesh J. Borad, Lewis R. Roberts
Molecular markers such as fluorescence in situ hybridization (FISH) and digital image analysis (DIA) have been shown to be particularly helpful in the nonsurgical distinction of benign from malignant biliary strictures in setting of negative routine cytology. [47] They allow for assessment of aneuploidy and chromosomal instability by detecting nuclear DNA and quantifying loss or gain of chromosomes, respectively[48]. In an evaluation of trisomy 7 as a marker of benign disease in PSC vs non-PSC patients, Levy et al. showed that FISH provided the greatest sensitivity (45%), while the sensitivity of DIA was comparable to routine cytology for patients with PSC and higher than routine cytology for patients without PSC. Composite DIA/FISH assessment provided a one- to fivefold increase over routine cytology. These results were consistent with another large study by Fritcher et al which demonstrated superior sensitivity of FISH over routine cytology for detecting biliary tract cancers[49]. In this study, FISH was able to detect 49/227 (22%) of biliary tract cancers initially interpreted as nonmalignant by routine cytology, without compromising specificity. Kipp et al further investigated and compared cytology and FISH to KRAS mutational analysis, given the incidence of KRAS gene alterations in 20–100% of patients with CCA [45,50]. This study revealed a sensitivity of 30% for KRAS mutation testing which improved to 54% when combined with FISH, again without compromising a specificity of 96% with both modalities[50].
Chromosomal radiosensitivity of triple negative breast cancer patients
Published in International Journal of Radiation Biology, 2019
Flavia Zita Francies, Olivia Herd, Alan Cairns, Sarah Nietz, Marshall Murdoch, Jacobus Slabbert, Kathleen B. M. Claes, Anne Vral, Ans Baeyens
Chromosomal instability in patients is characterized by an enhanced number of spontaneously occurring MN compared to the MN yields observed in healthy controls. The spontaneous MN values in the G0 MN assay of all breast cancer patients are significantly higher when compared to all healthy individuals (p = .0010) (Figure 2). The effect of age on chromosomal instability was investigated between all patients and all controls. No correlation was demonstrated in the MN values with age when comparing the young patients with the old (p = .7498) and young controls with the old controls (p = .1995). Enhanced MN values were significantly different for the young (p = .01) and older patients (p = .0062), TNBC (p = .0041) and luminal patients (p = .0066) compared to all controls indicating chromosomal instability (Figure 2). Data on smoking for these patients were analyzed and no effect of smoking was noticed on MN values in our study. As previously shown, there is no correlation between clinical parameters, such as tumor stage and grade, with chromosomal radiosensitivity (Baeyens et al. 2002).
Zoledronic acid induces cytogenetic toxicity in male germline cells of Swiss albino mice
Published in Drug and Chemical Toxicology, 2019
Ramakrishna Dasari, Sunil Misra
ZA generally binds and accumulates in the bone regions because of its affinity toward mineral hydroxyapatite of bone that ultimately helps in bringing about apoptosis of osteoclast cells (Roelofs et al.2010). Hence, due to its antiresorptive property, ZA has been the preferred choice for the treatment of malignancies associated with skeletal regions. Most of the cancer chemotherapeutic agents acts upon the rapidly proliferating cancer cells; however, these chemicals are also reported to cause undesirable toxicity to other normal cells of the body (Arif et al. 2009). Such undesirable toxic effects become more concerned when these genetic damages pass to the next generation in the form of defective gametes (Shalet et al. 1989). The toxic effects of traditional cytotoxic chemotherapeutic agents included in the treatment regime of cancer patients that lasts for long-periods appear in the form of gonadal toxicity in male individuals, which include persistent and delayed toxicity in the male reproductive system (Schilsky et al. 1980). Because of their tendency of causing DNA damages in spermatozoa, these chemicals can be regarded as highly toxic (Chatterjee et al.2000). Chromosomal instability is the result of errors in chromosome segregation (Bakhoum et al. 2009) and if there is a loss or gain of chromosomes in an embryo could lead to birth defects (Jones and Lane 2013). Hence, it is imperative to understand the possible clastogenic effect of ZA on the germline cells.