Oncogenes in Thyroid Tumors

Peter E. Goretzki, MD ■ Victor Gorelev, MD ■ Dietmar Simon, MD ■ Hans-Dietrich Roeher, MD

The knowledge that a variety of environmental conditions, such as exposure to external radiation or chemicals, or chronic inflammatory processes and viral infections can induce neoplasms initiated studies seeking the explanation for these associations. Cells can be infected with RNA- or DNA-containing viruses, and the viral genome becomes inserted into the genetic code of the host cell.1 As the cells divide, the viral DNA is transcribed and translated, producing a protein that may act as a growth factor, as a growth factor receptor, in signal transduction, or in the transcription of other genes. In the latter situation, it may interfere with apoptosis. Tumor development after viral infection occurs as a result of insertion and activation of viral oncogenes in host cells.1 Subsequent investigation documented that eukaryotic cells harbor genes similar to viral oncogenes, which started the hunt for additional protooncogenes.

Radiation and chemical toxins lead to tumor development and malignancy by causing multiple genetic changes that accumulate in affected cells (Fig. 30-1). These genetic changes may be single base pair changes (i.e., point mutations), insertions, deletions, rearrangements, and translocations. These genetic modifications affect encoded protein structure (i.e., mutations) or amplify certain genes (i.e., translocation), which then alter normal regulatory processes, turning protooncogenes into oncogenes.2

Protooncogenes can be defined as genes involved in cell growth and cell differentiation that gain oncogenic potential and support tumor development and tumor propagation when amplified or structurally modulated. Thyroid tumors of follicular cell origin appear to develop by means of multiple genetic changes in cells rather than by activation of a single oncogene.3,4 Oncogene products can be divided into different protein families with specific cellular functions (e.g., growth factor, growth factor receptor, signal-transducing protein), and they may act on cell surfaces, within the cell cytoplasm, or within the nucleus—that is, inhibitors and activators of transcription (Fig. 30-2).2'5

Some variations of these general rules are related to the physiologic characteristics of specific tissues. Oncogenes can be deduced from their similarity to viral genes and from genes encoding proteins involved in the physiologic pathways of cell stimulation.6"8 Constitutive activation by specific mutations was demonstrated in vitro for the thyroid-specific growth factor receptor (i.e., thyrotropin or thyroid-stimulating hormone [TSH] receptor) and the signal-transducing protein (gsp) connected to this receptor (i.e., alpha subunit of the Gs protein [Gs-a]).

The field of oncogene research focuses on genetics and incorporates information from microbiology (e.g., viral infectious diseases), embryology, physiology (e.g., proteins important in growth and differentiation), epidemiology (e.g., prevalence of thyroid cancer in Russia before and after the Chernobyl catastrophe), toxicology, and radiology (e.g., effect of radiation on oncogene structure and expression). In this chapter, we review the roles of oncogenes in human thyroid tumors.

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