Cancer Biology and Genetics for Non-Biologists
Trevor F. Cox in Medical Statistics for Cancer Studies, 2022
There are three special types of gene, proto-oncogenes, tumour suppressor genes and DNA repair genes. Their functions are: DNA repair genes do the job of repairing genes.Proto-oncogenes make proteins that stimulate cell division, inhibit cell differentiation (stop a cell changing) and preventing apoptosis. If a proto-oncogene mutates, it can become an oncogene that does the opposite to what it should be doing, and it can make a cell divide uncontrollably.Tumour suppressor genes slow down cell division, repair DNA and send signals to cells to die. When these mutate, they no longer suppress the tumour.
Carcinogenesis and Molecular Genetics
Peter G. Shields in Cancer Risk Assessment, 2005
Oncogenes are genes which act to stimulate cell division or increase cell survival, when expressed in a biochemically abnormal environment which is permissive for their growth stimulatory effects. When overexpressed or expressed aberrantly, they may disrupt the division–death ratio. Tumor suppressor genes have an equally important role in tissues, but in preventing in tumor formation. Normally, they protect cells from abnormal growth in several ways and, in cancers, are often found to be mutated so that their function is either altered or lost entirely. The complex interplay between oncogenes and tumor suppressor genes can be exemplified using the ras oncogene which becomes oncogenic by expressing altered function after a single base change, and the bcl-2 gene, which codes for a mitochondrial protein that helps prevent apoptotic cell death. Overexpression of a mutant ras oncogene is actually lethal to normal cells, but in the context of a cell which has lost expression of bcl-2, mutant ras becomes promitogenic (2).
Juvenile-Onset Recurrent Respiratory Papillomatosis
John C Watkinson, Raymond W Clarke, Christopher P Aldren, Doris-Eva Bamiou, Raymond W Clarke, Richard M Irving, Haytham Kubba, Shakeel R Saeed in Paediatrics, The Ear, Skull Base, 2018
Approximately 20 paediatric cases of malignant degeneration have been reported, all of which have been fatal. The currently proposed mechanism of malignant transformation involves oncoproteins E6 and E7. HPV types 6 and 11 produce transforming oncoproteins E6 and E7 that have been implicated in growth dysregulation through their ability to inactivate the tumour suppressor proteins p53 and the retinoblastoma tumour-suppressor gene product (pRb). The inactivation of the tumour suppressor genes results in a loss of control over proliferation and cell division and contributes to the development of the malignant phenotype. It is also becoming clear that the E6 and E7 proteins function to promote tumorigenesis through direct interactions with cell-cycle regulatory proteins.64 Unfortunately, apart from closer clinical and radiological surveillance particularly in children with tracheal and/or pulmonary disease, there is little to aid the clinician in predicting the rare cases of malignant transformation.65 There is no evidence of a papilloma–carcinoma sequence while p53 overexpression is variable and not a marker of malignant transformation.64 HPV expression may be lost in malignant transformation but this may not be a sufficiently robust clinicopathological predictor.
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].
Prospects of targeted and immune therapies in SCLC
Published in Expert Review of Anticancer Therapy, 2019
Lizza E. L. Hendriks, Jessica Menis, Martin Reck
SCLC has a high rate of somatic mutations: non-synonymous mutation rates of up to 8.6 mutations per million base pairs have been found [29,32]. They are often induced by smoking: benzo(a)pyrene (a carcinogenic compound of tobacco) and its active metabolite covalently binds to DNA, which can result in a DNA synthesis block leading to aberrant centrosome amplification. In turn, this can lead to abrogated p53 function and chromosome 3p deletion (which contains multiple tumor suppressor genes) [101–103]. This loss of tumor suppressor genes leads to increased mutagenesis. In 25% of SCLC patients, C:G > A:T transversions are found and they are an indication of heavy smoking [29,104]. Moreover, aberration of the intrinsic apoptotic pathway by inversion of the Bcl-2/Bax ratio results in further tumor growth [105]. Another signature found in SCLC which is linked to smoking and an increased mutagenesis is the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) signature [106].
Remodeling the cancer epigenome: mutations in the SWI/SNF complex offer new therapeutic opportunities
Published in Expert Review of Anticancer Therapy, 2019
Krystal A Orlando, Vinh Nguyen, Jesse R Raab, Tara Walhart, Bernard E Weissman
The finding of frequent mutations of subunits of the SWI/SNF chromatin remodeling complex by the TCGA and other tumor sequencing projects across a broad range of cancers has sparked renewed interest in targeting the epigenome with new treatment options. Because many of these mutations result in loss of function, efforts at identifying therapeutic vulnerabilities have suffered the same hurdles encountered for tumor suppressor genes such as BRCA1, RB1 or TP53. While recent studies have implicated the underlying mechanisms by which mutant SWI/SNF subunits can drive tumorigenesis, this knowledge has translated into limited novel treatment options. The only options that have led to drugs in clinical trials for these cancers have come from characterizing downstream signaling pathways altered by these mutations or through synthetic lethality screens of tumor cell lines. Therefore, accelerating the pace of research for understanding how mutations in SWI/SNF subunits drive the development of nearly 25% of human cancers should become a high priority.