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Diffuse Intrinsic Pontine Glioma
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Katherine E. Warren, Carolyn R. Freeman, Dannis G. van Vuurden
In contrast to adult high-grade gliomas43,44 and other pediatric CNS tumors such as medulloblastoma,45 the primary disease-determining aberrations in DIPG (histone mutations and their partners) appear to be spatially conserved, i.e., present in primary, contiguous, and metastatic sites of disease, and temporally preserved, present over the entire course of the disease.7,46 Tumor evolutionary studies suggest histone H3K27M mutations and their obligate partner mutations involving cell cycle or growth factor pathways arise first and remain present during tumor invasion and metastases.7 Whereas histologic-grade intratumoral heterogeneity is present and has no correlation with prognosis, genomic/molecular driver mutations are conserved, are spatially homogeneous, and do correlate with prognosis. This alleviates concerns about biopsy representation of tumor and is important when considering biopsy to determine treatment for patients. Additional oncogenic mutations may arise later and are subclonal.7
Radiation Hormesis in Cancer
Published in T. D. Luckey, Radiation Hormesis, 2020
Cellular repair mechanisms have also been observed to support hormesis. The well known example is DNA repair; this is replete with identified enzymes and metabolic reactions. DNA repair fails when: (1) a break occurs in the chromosome of a cell which is monoploid, e.g., an unfertilized egg or sperm cell which have only single stranded DNA, (2) relatively simultaneous breaks occur in both strands of DNA in the same area of a given chromosome, (3) a break occurs in one strand where the other carries a recessive gene for cancer or other disease, and (4) defective DNA is added to the chromosome from a viral infection. Failure to properly repair a break in DNA may allow any one of about 30 normal genes to be subtly transformed into an oncogene.22,924 Since each of our 50,000 genes contains 20,000 to 100,000 base pairs in a DNA chain, there is a big variety of combinations which can change normal genes into oncogenes. An oncogene releases the cell replication machinery from the limits which normally restrain growth. Some suspect the 30+ oncogenes have a common mechanism of action.982 A single cell can produce a well-defined tumor or form a metastasizing clone to establish cancer far removed from its original tissue.
Cancer: A Genetic Disease
Published in Jeremy R. Jass, Understanding Pathology, 2020
The relation between viral genes and cancer is clearly of importance, but research in this area drew attention to a still more important issue. Genes that were similar if not identical to the cancer genes of viruses were shown not to be exclusive to viruses but to reside in the cells of all species, including humans! The idea that we each carry genes that can cause cancer seems very strange until we realise that this is not the normal function of such genes. To cause cancer these genes need to be altered or mutated. The non-mutated genes are called proto-oncogenes, which are a large family responsible for the regulation of cell division (page 101). Oncogenes are mutated proto-oncogenes that may cause excessive cell division, one of the characteristics of a cancer cell. In summary, oncogenes can either be inserted into our cells by certain viruses, viral oncogenes (v-onc), or more commonly are the mutated forms of proto-oncogenes normally present within cells, cellular oncogenes (c-onc).
The current status of gene therapy in bladder cancer
Published in Expert Review of Anticancer Therapy, 2023
Côme Tholomier, Alberto Martini, Sharada Mokkapati, Colin P. Dinney
Over the last several decades, multiple genetic alterations have been implicated in bladder carcinogenesis. Specific genes include oncogenes, growth factors, antiapoptotic genes, cell proliferation factors, tumor suppressor genes, cell cycle inhibitors, apoptotic genes, cell adhesion molecules, and drug resistance genes [35]. They can be classified into three distinct groups based on their function in tumor development (Table 2). Knowledge around these genetic alterations allowed for development of gene therapy strategies for bladder cancer, which are summarized in Table 3. For example, oncogenes can be inactivated using antisense oligonucleotides (ASOs) or ribozymes (RZs). Both can be designed to target only the gene of interest [36]. Specific to bladder cancer, multiple groups developed specific ASOs and RZs targeting c-Fos, ERBB2, and MYC oncogenes, to inhibit cancer cell growth, or sensitize the tumors to platinum-based chemotherapy [37–39]. Inversely, restoration or even overexpression of tumor suppressor genes was found to be of benefit and lead to cancer cell death. Multiple studies have focused on induction of wild-type p53 through adenoviral vectors, including a study in bladder cancer [40–42]. Similar results of enhanced tumor suppressor gene therapy were shown with adenoviral vector delivering the wild-type retinoblastoma (Rb) gene in an in-vivo bladder cancer murine model [43].
Improving outcomes and quality of life for patients with transfusion-dependent β-thalassemia: recommendations for best clinical practice and the use of novel treatment strategies
Published in Expert Review of Hematology, 2021
Ali T. Taher, Rayan Bou-Fakhredin, Antonis Kattamis, Vip Viprakasit, Maria Domenica Cappellini
Among the emerging new treatment options, gene therapy has the potential to increase the number of patients who can receive curative treatment that can offer lifelong independence from RBC transfusions without the need for a matched sibling donor. For some countries, such as those with limited availability of donated blood, the wider availability of a treatment that reduces the need for RBC transfusions will be important. However, the fact that gene therapy is a very expensive and specialized treatment limits its use in many areas of the world. Health economic studies are needed to demonstrate the cost/benefit of gene therapy over a patient’s life. In addition, the long-term safety of gene therapy will need to be carefully monitored for the potential, though currently unsubstantiated, activation of oncogenes.
Ras-Mediated Activation of NF-κB and DNA Damage Response in Carcinogenesis
Published in Cancer Investigation, 2020
It is now well recognized that there are generally two classes of cancer genes, i.e., oncogenes (promote cell growth) and tumor suppressor genes (inhibit cell growth) (1,7). Oncogenes refer to those genes whose alterations result in the contribution to the defective malignant phenotype (30,31). The oncogenes are probably involved in both the initiation and progression of cancer, while the tumor suppressor genes after mutations or inactivation lead to the tumorigenicity (39–43). The activation of an oncogene may be in the form of chromosomal translocations, gene amplification, point mutations, or deletions (44–46). The activation of oncogenes involves genetic alterations to cellular protooncogenes which confers a growth advantage or increased survival of cells carrying such alterations. There are several mechanisms that activate oncogenes such as mutation, gene amplification, chromosome rearrangements, and altered expression of protooncogenes. These mechanisms result in either an alteration of protooncogene structure or an increase in protooncogene expression. The full expression of the neoplastic phenotype including the capacity for metastasis, usually involves a combination of protooncogene activation and tumor suppressor gene loss or inactivation. Since, carcinogenesis is a multistep process, any one of these mechanisms may contribute to the development of human tumors by altering the cancer-associated genes (31,42,47) (Figure 1).