The Mouse Skin as a Model for Chemical Carcinogenesis
John P. Sundberg in Handbook of Mouse Mutations with Skin and Hair Abnormalities, 2020
The molecular events related to the trisome of Chromosome 6 are poorly understood. No specific gene(s) has been identified that may be related to changes of this chromosome. However, recent results suggest that this chromosome may also harbor a tumor suppressor gene. This hypothesis is based in two independent pieces of evidence. Recent unpublished results seem to indicate that Chromosome 6 is a frequent target of allelic losses, usually a strong indication of the presence of a tumor suppressor gene in the region. The second piece of evidence is the recent identification by our laboratory of a region of human Chromosome 7 with close homology to murine Chromosome 6 that can suppress tumorigenicity of a murine carcinoma cell line. If confirmed, these results point to a possible correlation between trisomy and loss of heterozygosity by mitotic recombination by a still undetermined mechanism.
Beckwith–Wiedemann Syndrome
Dongyou Liu in Handbook of Tumor Syndromes, 2020
UPD is defined by the presence of two chromosomal regions from one parent and none from the other. Paternal UPD of 11p15.5 (Figure 86.1b) accounts for 20% of BWS cases and occurs only in sporadic cases. It generally affects both ICR1 and ICR2 and causes clinical phenotype due to overexpression of paternal alleles such as IGF2, and silencing of maternal alleles such as CDKN1C. Due to the significant changes in gene dosage, individuals with paternal UPD have a higher tumor risk, especially Wilms tumor and hepatoblastoma when compared to BWS patients in general [18]. In BWS, paternal UPD occurs as a post-fertilization mitotic recombination event and exhibits somatic mosaicism; thus, the higher level of UPD cells in specific organs and tissues should theoretically associate with a more severe phenotype [19]. This was corroborated by two cases of BWS with extremely high levels of UPD in DNA from lymphocytes. Both of them presented with extreme macroglossia, persistent hypoglycemia, cardiomyopathy, and hepatoblastoma, and died in the first 6 months of life [20]. Recently, a novel molecular abnormality was described in BWS patients in whom additional features of UPD, including premature thelarche, conjugated hyperbilirubinemia, and atypical tumors, were presented. Mosaic genome-wide paternal UPD—characterized by a mosaic blend of paternal uniparental and biparental cell lineages—was discovered by SNP array testing [21]. The findings expand our knowledge of the defective molecular spectrum of BWS and emphasize the importance of a degree of mosaicism in phenotypic variability.
Molecular Approaches Towards the Isolation of Pediatric Cancer Predisposition Genes
John T. Kemshead in Pediatric Tumors: Immunological and Molecular Markers, 2020
Demonstration of the generation of homozygosity in the tumors of retinoblastoma patients who were constitutionally heterozygous for the same DNA “markers” was followed closely by the same observation in Wilms’ tumors. Using 11p distal probes, several groups showed that, in a proportion of tumors, homozygosity was generated.96–98 The mechanism was shown not to be due to simple chromosome loss, but to nondisjunction or, in one case99 mitotic recombination. Analysis of tumor material from one of our own patients with an 11pl3-pl5 deletion showed that the tumor had retained a copy of the catalase gene, excluding the possibility that a large homozygous deletion had been generated in these cells.
Assessment of the mutagenic, recombinogenic, and carcinogenic potential of amphotericin B in somatic cells of Drosophila melanogaster
Published in Drug and Chemical Toxicology, 2018
Rosiane Soares Saturnino, Nayane Moreira Machado, Jeyson Cesary Lopes, Júlio César Nepomuceno
It is possible that this carcinogenic activity found in our study is due to mechanism of homologous recombination as shown by SMART. Although homologous recombination is an important process for DNA repair, there is an increasing evidence that deleterious genomic rearrangements may result from homologous recombination, which may be crucial in carcinogenesis (Arossi et al., 2009). The transformation of normal cells into cancer cells is a multi-step process and the mitotic recombination is a mechanism involved in the determination of this transformation (Barrett, 1993; Nowell, 1976). In heterozygous cells having both mutant and normal alleles for a tumor suppressor gene, somatic recombination can be a promoter of neoplasia by inducing homozygosis of the mutant tumor suppressor allele (Maher et al., 1993; Sengstag, 1994).
Evolving paradigms for the biological response to low dose ionizing radiation; the role of epigenetics
Published in International Journal of Radiation Biology, 2018
Paul N. Schofield, Monika Kondratowicz
TEs make up very large portions of the mammalian genome and are defined as ‘mobile genetic elements that move around within the genome of an organism’ (Bestor 2005). A global loss of DNA methylation, altered levels of DNMTs, and methyl-binding proteins have been linked to their activation which contributes to genomic instability (GI) and increased mutation rates (Merrifield and Kovalchuk 2013). Genomic instability after genome hypomethylation makes perfect sense if one considers the role that DNA methylation has in regulation of mitotic recombination, centromeres, telomeres, and in silencing gene expression. Hypomethylation of TEs alone is considered adequate for this phenomenon which has been linked with a higher risk of developing cancer) (Kaup et al. 2006) although interestingly, repetitive element hypomethylation observed in bone marrow mononuclear cells (Miousse et al. 2014) did not correlate with any difference in TE expression, suggesting a possible silencing role of histone modifications and/or small regulatory RNAs which overrides methylation status in some instances. However, activation of LINE sequences in response to irradiation has been demonstrated in rat mammary tissues (Luzhna et al. 2015). Although aberrant reactivation of retrotransposons LINE1 and SINEB2 could lead to genome amplification, insertions, deletions, and altered contiguous gene expression, so far there has been no evidence of increased ‘copy-and-pasting’ after low dose irradiation as suggested by (Ilnytskyy et al. 2009).
Nanoparticles as a potential teratogen: a lesson learnt from fruit fly
Published in Nanotoxicology, 2019
Bedanta Kumar Barik, Monalisa Mishra
Cu NPs having myriads of usage (Hajipour et al. 2012; Bondarenko et al. 2013) can induce toxicity in Drosophila (Carmona, Inostroza-Blancheteau et al. 2015). CuO NPs proved to be genotoxic to Drosophila as it causes DNA damage to larval haemocyte. CuO NPs causes mitotic recombination a potential mechanism to cause mutation. Malondialdehyde, a marker for oxidative stress, was found to be increased after CuO NP exposure. The oxidative stress can bring about genotoxicity in Drosophila. CuO NP further causes developmental delay,which is associated either with genotoxicity or with oxidative stress. Han et al. (2014) also reported that Cu NPs causes developmental delay, reduced adult longevity, and sperm competition in Drosophila. CuO NPs resulted reduced larval growth, defective metamorphosis, and delayed pupa to adult stage (Alaraby et al. 2016). The toxicity is due to the copper ions released from the CuO NPs. Genetic markers such as Dual oxidase (Duox), Hemolectin (Hml), Prophenoloxidase 2 (PPO2), and Unpaired 3 (Upd3) in gut cells are downregulated due to the effect of CuO NP. Accumulation of CuO NPs in the gut lumen, gut cells, and haemocytes (after translocation) decreased the microbiota population within the gut.