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Molecular Approaches Towards the Isolation of Pediatric Cancer Predisposition Genes
Published in John T. Kemshead, 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.
The Mouse Skin as a Model for Chemical Carcinogenesis
Published in John P. Sundberg, 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 Recent unpublished results seem to indicate that Chromosome 6 is a frequent target of allelic losses, usually a strong indication of the presence of a tumor suppressor gene in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.
Transformation of Colon Epithelial Cells
Published in George E. Milo, Bruce C. Casto, Charles F. Shuler, Transformation of Human Epithelial Cells: Molecular and Oncogenetic Mechanisms, 2017
Familial polyposis, an autosomal-dominant disorder in humans, is characterized by the occurrence of numerous adenomas in the colon, a predisposition to the development of colorectal tumors.101 The gene linked to familial polyposis has been localized to chromosome 5q.102,103 Allelic losses on chromosome 5 of colonic adenomas and tumors derived from patients with and without familial polyposis were recently analyzed.24 None of the 34 adenomas of polyposis patients showed an allelic loss. In contrast, 29% of the adenomas and 36% of the carcinomas from patients without polyposis had allelic losses on chromosome 5. Further, approximately 37% of the adenomas smaller than 1 cm also exhibited such allelic losses. These results suggested that the allelic deletions involved in the adenoma development are not the same as those associated with familial polyposis.24 In fact, mitotic recombination and deletion experiments demonstrated that the alleles lost in the tumors are different from those previously linked to polyposis.24 These data are at variance with other inherited disorders such as retinoblastoma, where specific allelic deletions are linked to the development of the tumors.104,105 If the familial polyposis locus is not involved in colorectal tumors, how is the gene involved in adenoma production? It has been suggested that this locus may normally be responsible for negative regulation of the epithelial cell proliferation.24 Inactivation of the one allele probably results in the inefficient control of cell proliferation, creating a selective growth advantage for cells harboring the allelic deletions. The transition from the hyperplastic epithelium to adenoma may involve additional events such as the ras gene mutations. In this respect, approximately 25% of the adenomas from polyposis patients reportedly had ras gene mutations or allelic losses of chromosomes 17 or 18.24
Combining metaphase cytogenetics with single nucleotide polymorphism arrays can improve the diagnostic yield and identify prognosis more precisely in myelodysplastic syndromes
Published in Annals of Medicine, 2022
Yao Qin, Hang Zhang, Lin Feng, Haichen Wei, Yuling Wu, Chaoran Jiang, Zhihong Xu, Huanling Zhu, Ting Liu
Acquired CN-LOHs have been described in several haematological disorders, including MDS, myeloproliferative diseases, and AML [7, 22–24]. A previous study found CN-LOH were frequently detected on chromosomes 6, 11, 4, and 7 [11]. Acquired CN-LOH is likely the result of mitotic recombination and appears to be a common event in MDS [20]. Besides, acquired CN-LOH helps to identify gene mutations associated with MDS and related diseases. Such as, CN-LOH (4q24) in MDS promoted the discovery of TET2 gene mutation [25]; CN-LOH (11q) in CMML promoted the identification of CBL gene mutation [26, 27], and CN-LOH (17p) in MDS/sAML promoted the confirmation of TP53 gene mutation [28]. In our study, 21 patients (19.1%) with acquired CN-LOH were detected by SNP-A, mostly on chromosomes 17, 7, 11 and 21, which were consistent with those found by Tiu et al. [7]. Therefore, CN-LOH abnormalities can make up for the inability of MC karyotyping.
Modulating effect of a hydroxychalcone and a novel coumarin–chalcone hybrid against mitomycin-induced genotoxicity in somatic cells of Drosophila melanogaster
Published in Drug and Chemical Toxicology, 2022
Jefferson Hollanda Véras, Camila Regina do Vale, Débora Cristina da Silva Lima, Murilo Machado dos Anjos, Aline Bernardes, Aroldo Vieira de Moraes Filho, Carolina Ribeiro e Silva, Guilherme Roberto de Oliveira, Caridad Noda Pérez, Lee Chen-Chen
SMART measures loss of heterozygosity induction, which may occur through a variety of mechanisms such as point mutations, chromosome mutations, and mitotic recombination (Thomé et al. 2012). Homologous recombination (HR) is responsible for loss of heterozygosity, which are also involved in the regulation of cell cycle. The HR can also induce events such as gene conversion, deletion of chromosomal segments and translocations and it is also one of the main factors in the origin and progression of carcinogenic processes. Therefore, the relevant antirecombinogenic effects of 2HMC and 4-MET observed in this study are of great importance since this outcome shows a possible use of these molecules in therapies that aim to prevent or reduce the DNA damage. Thus, these compounds have a profile for the development of chemopreventive drugs against damage caused by genotoxic agents.
Assessment of bendamustine-induced genotoxicity in eukaryotic cells
Published in Drug and Chemical Toxicology, 2019
Tais Susane Pereira, Juliane Rocha de Sant’anna, Janicelle Fernandes Morais, Joana Paula Rocha de Sant’anna Yajima, Paulo Cezar de Freitas Mathias, Claudinéia Conationi da Silva Franco, Marialba Avezum Alves de Castro-Prado
Since DNA mutation and somatic recombination play important roles in the tumorigenic process and since the bendamustine interaction with DNA appears to be more complex than other cytotoxic agents (Leoni et al. 2008, Stewart et al. 2012, Spaans et al. 2014), the current study assesses the cytotoxic, mutagenic, and recombinogenic potentials of bendamustine in eukaryotic cells. Bendamustine’ cytotoxicity and mutagenic potential were investigated in human lymphocytes by mitotic index (MI) assay, in vitro mammalian cell micronucleus (Mnvit) test, and the chromosomal aberrations (CA) test. Further, since the homologous recombination is a critical process in the repair of damages that occur during DNA replication, including double-strand break, and since the homologous recombination is an inducer of LOH (loss of heterozygosity), a process involved in cancer development, the recombinogenic potential of bendamustine was also evaluated in the current study by the in vivo homozygotization assay, which detects LOH due to the mitotic recombination in diploid cells of Aspergillus nidulans (Pires and Zucchi 1994).