Human Esophageal Epithelial Cells: Immortalization and In Vitro Transformation
George E. Milo, Bruce C. Casto, Charles F. Shuler in Transformation of Human Epithelial Cells: Molecular and Oncogenetic Mechanisms, 2017
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
Soft tissue sarcomas
Pat Price, Karol Sikora in Treatment of Cancer, 2014
Cytogenetic analysis is now being performed more frequently on sarcomas. It is a diagnostically useful technique because some sarcomas have specific cytogenetic alterations which appear to be pathognomonic. For instance, 83% of Ewing’s sarcoma/primitive neuroectodermal tumours have a characteristic t(11;22) translocation and 50% of alveolar rhabdomyosarcomas show a t(2; 13) translocation.38,204,205 Myxoid liposarcomas have been found to have a t(12;16) translocation; clear cell sarcoma a t(12; 22) translocation; extra-skeletal myxoid chondrosarcoma a t(9;22) translocation and synovial sarcomas a t(x;18) translocation.173 Characteristic cytogenetic changes are also found in infantile fibrosarcomas and dermatofibrosarcoma protuberans. Structural abnormalities of chromosome 1p have been found in 70%–80% of neuroblastomas. They are often associated with double minute chromosomes or homogeneously staining regions (sites of amplification of complex rearranged genes), including a core of multiple copies of N-MYC oncogene. Aside from being helpful in diagnosis, the findings of these 1p rearrangements and double minute chromosomes further denote a poor clinical outcome.206
Molecular Approaches Towards the Isolation of Pediatric Cancer Predisposition Genes
John T. Kemshead in 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.
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.
Experimental drugs in clinical trials for acute myeloid leukemia: innovations, trends, and opportunities
Published in Expert Opinion on Investigational Drugs, 2023
Aleksandra Gołos, Joanna Góra-Tybor, Tadeusz Robak
Murine Double Minute 2 (MDM2) is a ubiquitin ligase that negatively regulates TP53 [92]. MDM2 is overexpressed in AML, leading to the inactivation of TP53 irrespective of its mutational status [93]. Idasanutlin (RG7388) is a novel, more selective, and potent MDM2 inhibitor, which showed promising results in early-phase clinical trials [94]. However, a phase 3 MIRROS (NCT02545283) study of idasanutlin with cytarabine was terminated due to the failure to achieve its primary endpoints [95]. Idasanutlin is currently being investigated in a phase I study in combination with venetoclax in RR AML (NCT02670044). The interim analysis showed an ORR of 41% with a median time duration of 4,9 months [96]. Two other MDM2 inhibitors are in early-stage clinical trials: AMG323 in monotherapy and in combination with trametinib and decitabine and DS3032s with azacitidine (NCT02319369) [97].
The potential diagnostic and prognostic role of extracellular vesicles in glioma: current status and future perspectives
Published in Acta Oncologica, 2019
Zulfikar Azam, Véronique Quillien, Gang Wang, Shing-Shun Tony To
Glioblastoma (GB), the deadliest and most prevalent form of brain tumor, arises from glial cells with an incidence rate of 3.2 per 100,000 populations [1] and the numbers are increasing every year [2]. GB can develop as primary tumor (de novo) without known clinical/histological evidence, or secondarily from low-grade tumors by transformation. Most GB are primary which occur predominantly in older patients and have poorer prognosis [3]. Genetic changes vary in GB, for example, IDH1 mutation is evident in secondary GB only [4] and p53 mutations are more common in secondary GB than primary [5]. Other common mutations in GB include, epidermal growth factor receptor (EGFR) (40–57%) [6], platelet-derived growth factor receptor (60%) [7], mouse double minute homolog 2 (10–15%) [5], the phosphatase and tensin homolog (PTEN) gene (20–34%) [8], NF1 (13.7%) [9], and PIK3CA (12%) [9]. Loss of heterozygosity on the chromosome arm 10q accounts for 60–90% in all GB cases [10]. Based on these genetic variances and their gene expression, GB can be further divided into four subtypes, namely, proneural, neural, classical and mesenchymal [11,12]. Distinct genetic and epigenetic variations are associated with each subtype that may be a result of intra-tumor heterogeneity [13].
Related Knowledge Centers
- Adaptation
- Chromothripsis
- Drug Resistance
- Gene Duplication
- Oncogene
- Neoplasm
- Neuroblastoma
- Extrachromosomal DNA
- Gene
- Chromosome