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Oncogenes and tumor suppressor genes
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
S. Giordano, S. Corso, P. Conrotto
What mechanisms are responsible for such activation? Conversion, or activation, of a protooncogene into an oncogene generally involves a gain-of-function mutation (Figure 5). At least three mechanisms can produce oncogenes from the corresponding proto-oncogenes: Point mutations or small deletions in the coding sequence, resulting in a constitutively activated protein;Gene amplification, resulting in overexpression of the normal protein;Chromosomal translocations, bringing the proto-oncogene under the control of an active promoter, causing inappropriate expression of the gene.
Genomics and Hearing Loss: Toward a New Standard of Care?
Published in Stavros Hatzopoulos, Andrea Ciorba, Mark Krumm, Advances in Audiology and Hearing Science, 2020
Research on future treatments of genetic hearing loss has already started and is mainly based on the two major classes of genetic mutations, loss-of-function, and gain-of-function. In loss-of-function mutations, the most common form, the protein product of a gene is either missing, nonfunctional or reduced in quantity. These are typically recessive mutations, because a normal allele can usually compensate for the nonfunctional one. In contrast, the altered gene product takes on a new molecular function in gain-of-function mutations, which usually follows dominance inheritance, because the presence of a normal allele is not capable of preventing the mutant allele from behaving abnormally. One subtype of the gain-of-function mutation is the dominant-negative mutation, when the product of a mutant gene competes with or inhibits the function of the normal product.
Personalized Medicine in Hereditary Cancer Syndromes
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
The RET oncogene encodes a transmembrane tyrosine kinase receptor with an extracellular domain, a transmembrane domain, and an intracellular tyrosine kinase region [35]. The gain of function mutation seen in inherited MTC can affect both extracellular and intracellular regions. Mutation in the extracellular cysteine-rich domain leads to ligand independent dimerization of the receptors and downstream activation of the intracellular pathway while mutations in the intracellular tyrosine kinase region leads to constitutive activation of intracellular pathways [33, 35].
Porphyria: awareness is the key to diagnosis!
Published in Acta Clinica Belgica, 2022
Benjamin Heymans, Wouter Meersseman
There are actually two forms of protoporphyria: erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP). The molecular basis of EPP is a reduction (up) to less than 30% of the enzyme catalyzing the last step in the haem biosynthesis, ferrochelatase. EPP is an autosomal recessive disease, caused in the majority of cases by a combination of full inactivation of one allele and a faulty splicing of the mRNA of the other allele, further reducing the expression of the enzyme. In a minority of cases, a mutation in both alleles is present [13]. By contrast, in XLP with X-linked inheritance there is a gain-of-function mutation in delta-aminolevulinic acid synthase 2. This results in an overproduction of protoporphyrin. Part of this excess is transformed by ferrochelatase to zinc-bound protoporphyrin.
Systemic therapy of advanced/metastatic gastrointestinal stromal tumors: an update on progress beyond imatinib, sunitinib, and regorafenib
Published in Expert Opinion on Investigational Drugs, 2021
Mahmoud Mohammadi, Hans Gelderblom
Although gastrointestinal stromal tumors (GISTs) are a rare type of cancer with an incidence of around 15 patients per million per year [1], they are the most prevalent mesenchymal neoplasm. Reported incidence rates of GIST are variable across different geographical regions, although most population-based studies share similar epidemiological features of GIST around the globe [2]. At diagnosis, patients have a median age of mid-sixties with a slight predominance in males [1]. While GIST can arise along the entire gastrointestinal tract, most primary are found in the stomach (56%) and in the small intestine (32%). The minority of GISTs is located in the colon and rectum (6.0%), esophagus (0.7%), and other sites (5.5%) [2]. The recognition of overexpression of the KIT protein, a receptor tyrosine kinase, also known as CD-117 was crucial for accurately diagnosing GIST more than two decades ago. Simultaneously, the discovery of a gain of function mutation resulting in uncontrolled activation of KIT was a practice-changing breakthrough [3]. These mutations in KIT or platelet-derived growth factor receptor (PDGFRA) genes lead via activation of sustained growth, proliferation, and inhibition of apoptosis to – development of GIST [3,4]. Approximately 80% of GISTs arise from oncogenic KIT mutations while PDGFRA mutations are in 10–15% responsible for GIST. In the remaining 5–10% of GIST, the formally so-called wild-type GIST, other stigmata such as SDH-deficiency, NF1 mutation, and occasional NTRK and BRAF mutations are identified.
Glioblastoma multiforme: novel therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2020
Matthew Muir, Sricharan Gopakumar, Jeffrey Traylor, Sungho Lee, Ganesh Rao
Recent sequencing data have shown that 57% of GBM show evidence of gain of function mutation and/or focal amplification of EGFR [8]. EGFR is activated by ligands such as EGF, transforming growth factor alpha, heparin-binding EGF-like growth factor, amphiregulin, epiregulin, betacellulin, and epigen [9]. Ligand binding induces receptor dimerization and auto-phosphorylation by the intracellular tyrosine kinase domain, resulting in recruitment of effector proteins and activation of downstream signaling cascades including phosphoinositide 3-kinase, mitogen-activated protein kinase, and signal transducer and activator of transcription 3 (STAT3) pathways. The most frequently occurring EGFR mutation in GBM, EGFRvIII, contains a deletion within the extracellular domain of the receptor that renders it constitutively active. Importantly, single cell sequencing studies showed that wild-type and mutant forms of EGFR are almost mutually exclusive, with only 1-2% of cells co-expressing wild type EGFR and EGFRvIII [10].