Resistance Mechanisms of Tumor Cells
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Almost all hematological tumors do not exhibit such a mutational landscape rather than display recurrent chromosomal translocations that result in “chimeric fusion genes” (see Fig. 17.1, upper right panel B). These fusions genes are highly specific and prototypic for leukemia disease subtypes (ALL, AML, CML, and CLL). The term “chromosomal translocation” describes an illegitimate exchange of chromosome material between two or more non-homologous chromosomes. In most cases, these illegitimate events are caused by a DNA damage situation where a subsequent DNA repair process results in wrongly fused “derivative chromosomes” (Reichel et al., 1998; Richardson et al., 1998). Chromosomal translocations can be subcategorized by the results of their illegitimate recombination event: (1) overexpression of proto-oncogenes by fusing them to strong enhancers, or (2) creation of chimeric fusion genes. Since these chromosomal changes occur recurrently at nearly precise points of our genomes, one might argue that these genes represent recombination hot spots. DNA damage situation may occur more frequently due to endogenous events (like, e.g., early apoptosis, torsional stress, DNase I hypersensitive sites, etc.) or exogenous xenobiotic stress conditions (Strick et al., 2000).
Oncogenes and Cancer
Pimentel Enrique in Oncogenes, 2020
Although it is frequently assumed that chromosome translocations can cause cancer through activation of proto-oncogenes there are at least three good reasons for caution in generalizing this deduction and accepting it uncritically:277 (1) activation of an oncogene as a result of translocation has yet to be demonstrated as a general phenomenon; (2) even it it were, it would be premature to accept it as the cause of malignant transformation in vivo, and (3) the specificity of most of the chromosome abnormalities reported in leukemias and lymphomas is not absolute. Proto-oncogenes are relatively evenly distributed among the different types of human chromosomes. The possibility should be considered that at least certain associations between a numerical and/or structural alteration of a particular chromosome and a given type of tumor may be independent of the presence of proto- oncogene(s) in the chromosome.
Medical Care of the Child with Down Syndrome
Merlin G. Butler, F. John Meaney in Genetics of Developmental Disabilities, 2019
About 3% of individuals with DS are found to have a chromosome translocation, in which the extra chromosome 21 is attached to either a chromosome number 13, 14, 15, 21, or 22 (Fig. 2). Although 50% of chromosome translocations occur de novo, the other 50% are inherited from a parent who is a balanced carrier (i.e., the parent has one of their chromosome 21’s attached to another chromosome). This parent (mother or father) can transmit the translocated chromosome to a subsequent child in an unbalanced fashion (and have another child with DS), or in a balanced fashion to the affected child’s siblings, who would be at risk for having a child of their own with DS if the chromosome translocation is inherited in an unbalanced fashion. Table 1 shows the empiric recurrence risk for the parents depending on the chromosome translocation status and parent of origin. Consequently, it is necessary to obtain a karyotype of both parents of children with translocation DS to determine the type of chromosome translocation, if present, which impacts on the recurrence risk.
AID Biology: A pathological and clinical perspective
Published in International Reviews of Immunology, 2018
Meenal Choudhary, Anubhav Tamrakar, Amit Kumar Singh, Monika Jain, Ankit Jaiswal, Prashant Kodgire
Chromosomal aberrations have been discovered about hundred years ago and associated with cancer development [114]. By definition, chromosomal translocations involve the exchange of genetic information between two non-homologous chromosomes [115]. The most important aspect of chromosomal translocation lies in its cause for genomic instability and cancer. It is, therefore, the most critical aberrations causing structural changes in two heterologous chromosomes. It is interesting to understand the underlying mechanism of chromosomal translocation and factors that affect the event in the cell such as the frequency of occurrence of DNA DSBs and the proximity of two translocating loci in the genome. Translocation can also occur in between the coding region of two genes, leading to the formation of a chimeric fusion gene product [116]. Genome-wide chromosomal translocations occur as a random event that allows joining of two unrepaired broken chromatin ends that show significant movement, thus indicating that DSBs can move freely in the nucleus [117]. Several factors underlie the mechanism of chromosomal translocation. Generation of DSBs is a necessary event for initiation of translocation. DSBs can be formed because of genotoxic stress, cellular stress or by some endogenous genetic alteration caused by enzyme AID as discussed above [118]. Spatial proximity of the translocating genes is another important factor that has been correlated with the frequency of occurrence of chromosomal translocation [118]. It has mainly been investigated in Burkitt's lymphoma, thyroid lymphoma, promyelocytic and acute myelocytic leukemia [119].
Chronic low dose exposure of hospital workers to ionizing radiation leads to increased micronuclei frequency and reduced antioxidants in their peripheral blood lymphocytes
Published in International Journal of Radiation Biology, 2019
Zothan Siama, Mary Zosang-zuali, Annie Vanlalruati, Ganesh Chandra Jagetia, Kham Suan Pau, Nachimuthu Senthil Kumar
The MN assay has been used as a quantitative indicator of X-ray induced chromosome damage in several studies, both in vitro and in vivo (Ramalho et al. 1998; Maffei et al. 2002; Joseph et al. 2004; Ropolo et al. 2012; Koyama et al. 2016). Our results indicate that the mean MNBNC frequency was significantly higher in exposed workers than in controls irrespective of their demographic characteristics. Our findings are in agreement with other studies on occupational workers from China, Korea and Romania population, where a higher MN frequency has been reported after exposure to chronic low doses of ionizing radiation (An and Kim 2002; Mihalache et al. 2007; Sahin et al. 2009; Eken et al. 2010; Zakeri and Hirobe 2010; Sakly et al. 2013; Qian et al. 2016; Gharibdousty et al. 2017; Lusiyanti et al. 2017). The radiological technicians also showed an increase in chromosome translocations in a US study (Sigurdson et al. 2008). In contrast, some studies did not find any increase in the MN frequency in the exposed group as compared to controls, which may be due to several other confounding factors (Demirel et al. 1997; Thierens et al. 2000). Our results further indicated a strong association between MNBNC frequency and the duration of working with IR (X-rays), number of patients handled by a radiology worker per day and the age of the exposed group (Table 4).
Genetic variations as molecular diagnostic factors for idiopathic male infertility: current knowledge and future perspectives
Published in Expert Review of Molecular Diagnostics, 2021
Mohammad Karimian, Leila Parvaresh, Mohaddeseh Behjati
Balanced chromosomal translocations involve the breakage of two chromosomes and abnormal repair of chromosomal fragments resulting in the transfer of genetic material from one chromosome to another without loss of any genetic material. In vast majority of cases, carriers of balanced translocations are phenotypically normal, unless one of the breakpoints at the site of translocation disrupts an important gene. Chromosomal translocation, while phenotypically normal, may experience fertility loss, miscarriage, or birth defects. Normal meiotic segregation of these translocations in gametes can lead to duplication or deletion of chromosomal regions involved in translocation [171]. Like chromosomal translocations, inversions can lead to infertility, miscarriage, and birth defects. During meiosis, chromosomes are forced to form specialized structures, so that homologous chromosomes can be paired. Chromosomal inversions can affect these specialized structures. Research on the production of unbalanced gametes in balanced inversion carriers has been done to a much lesser extent than translocations. However, a handful of studies have reported an unbalanced sperm range of 1–54% [172–174].
Related Knowledge Centers
- Chromosome Abnormality
- Cytogenetics
- Fusion Gene
- Karyotype
- Gamete
- Genetics
- Chromosome
- Cell
- Gene
- Prenatal Testing