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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
Analysis of chromosome translocations has failed to implicate the involvement of any oncogene in the genesis of Rb although dosage studies in tumors have shown an elevated level of the N-myc oncogene in one case associated with double minute chromosomes.26One cell line, Y79, contains a homogeneously staining chromosome region.37,38 Both these chromosome abnormalities have been shown to represent the cytological manifestation of gene amplification.39 Squire et al.26 were able to analyze chromosomes in tumors from different foci in the same patient, but failed to reveal a consistent pattern of chromosome abnormality suggesting that most of these changes probably represent events associated with progression, rather than with initiation of the tumor. Squire et al.40 confirmed this suggestion with the analysis of N-myc expression in normal and tumor tissue. Only tumors showing genomic amplification of N-myc had elevated mRNA levels. N-myc expression was present in normal adult tissues, including brain and retina, and N-myc mRNA levels in retinoblastoma cells were the same as those seen in normal fetal tissue. Thus N-myc expression in tumors probably reflects the origin of the cells rather than indicating a role in oncogenic transformation.
Mechanisms of Resistance to Antineoplastic Drugs
Published in Robert I. Glazer, Developments in Cancer Chemotherapy, 2019
Philip J. Vickers, Alan J. Townsend, Kenneth H. Cowan
Instead of the development of HSRs, gene amplification may be associated with the development of structures known as double minute chromosomes (DMs).109 DMs are small, usually paired, circular pieces of chromatin. In contrast to HSRs, DMs contain no centromeres and therefore separate unequally into replicating daughter cells. Consequently, DMs are readily lost from cells when they are grown in the absence of selective pressure. Therefore, when drug resistance is associated with amplified genes located on DMs, the resistant cell may revert to a drug-sensitive state within a short period if not cultured under selective pressure.
Human Esophageal Epithelial Cells: Immortalization and In Vitro Transformation
Published in George E. Milo, Bruce C. Casto, Charles F. Shuler, Transformation of Human Epithelial Cells: Molecular and Oncogenetic Mechanisms, 2017
Gary D. Stoner, Zenya Naito, George E. Milo
The conversion of normal human esophageal epithelial cells to cancer cells is associated with a variety of genotypic and phenotypic alterations. Cytogenetic studies using human esophageal carcinoma cell lines revealed frequent structural abnormalities (usually deletions) in chromosomes 1, 3, 9, and 11.15 In addition, there was evidence of gene amplification in the form of homogeneously staining regions and double-minute chromosomes in primary and metastatic tumors.16 Molecular studies revealed amplification of the epidermal growth factor receptor gene (c-erbB),17 and coamplification of the hst-1 and int-2 genes in esophageal carcinomas.18 Elevated levels of the EGF receptor appears to be associated with the malignant potential of these tumors.19 There was no evidence for point mutations in codons 12, 13, or 61 in the H-, K- or N-ras genes in human esophageal carcinomas.20
Large extracellular vesicles carry most of the tumour DNA circulating in prostate cancer patient plasma
Published in Journal of Extracellular Vesicles, 2018
Tatyana Vagner, Cristiana Spinelli, Valentina R. Minciacchi, Leonora Balaj, Mandana Zandian, Andrew Conley, Andries Zijlstra, Michael R. Freeman, Francesca Demichelis, Subhajyoti De, Edwin M. Posadas, Hisashi Tanaka, Dolores Di Vizio
Using an approach that allows to estimate the size of the intact DNA fragments in EVs, we showed that L-EVs contain unusually high molecular weight DNA. This is the first DNA evaluation directly in intact EVs. Similar size DNA has been reported to derive from DNA damage and likely chromosomal fragmentation that occurs in micronuclei, which can induce chromothripsis [42]. Chromothripsis consists of massive clustered chromosomal rearrangements usually involving one chromosome. This process can induce the formation of double minute chromosomes, which are extrachromosomal circular DNA structures harbouring amplified oncogenes [43–46]. Given the size of L-EVs and their tumour-specific origin, it seems plausible that the extrachromosomal DNA from the cytosol of cancer cells is loaded in L-EVs forming at the plasma membrane. This hypothesis, although speculative, is supported by our data showing that L-EV DNA is chromatinized. However, the molecular mechanisms of DNA loading into EVs are largely unknown and need to be further explored. The nature of L-EV DNA could be interrogated by sequencing the high molecular weight DNA strands, which are uniquely present in L-EVs, to investigate if they are enriched in particular sequences (e.g. amplified oncogenes). In addition, this might also provide some cues to L-EV biogenesis.