Proto-oncogenes and carcinogenesis
Proto-oncogenes are normal cellular genes that, when mutated or expressed abnormally, can become oncogenes, which are responsible for promoting cancer. These genes play crucial roles in regulating cell division, differentiation, and programmed cell death (apoptosis). Alterations such as chromosomal translocations, point mutations, or gene amplifications can lead to the transformation of proto-oncogenes into oncogenes, driving neoplastic growth and tumor development. For instance, specific mutations in the BCL2 proto-oncogene can lead to B-cell lymphomas by preventing apoptosis and enabling cancerous cell proliferation. Additionally, other cancers such as T-cell lymphomas and nephroblastoma also illustrate the significance of proto-oncogenes, with distinct genetic alterations contributing to their pathogenesis. The historical context of proto-oncogenes reveals their discovery in retroviruses and the subsequent understanding that these cancer-causing genes are derived from normal host cell genes. Today, over a hundred oncogenes have been identified, with some, like KRAS, being implicated in a significant percentage of various human cancers. Understanding proto-oncogenes is essential in cancer research, as they highlight critical pathways involved in tumorigenesis.
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Subject Terms
Proto-oncogenes and carcinogenesis
ALSO KNOWN AS: Precursors of oncogenes
DEFINITION: Proto-oncogenes are cellular genes that may be transformed into oncogenes (cancer-causing genes). Proto-oncogenes provide signals that promote the division and specialization of normal cells or regulate programmed cell death (apoptosis). Changes in their genetic sequence or expression level due to chromosomal translocation, point mutation, or amplification can trigger a sequence of events leading to a cell's neoplastic transformation (abnormal growth) and subsequently to tumor formation. Gene mutations, epigenetic changes, chromosome rearrangements, and gene mutations are ways oncogenes can be activated.
Etiology and symptoms of associated cancers: B-cell lymphomas are caused by B-cell lymphocytes. Through a chromosomal translocation, the BCL2 proto-oncogene may become rearranged, resulting in overexpression of its protein product. The protein product blocks apoptosis, thereby enabling continued growth of the malignant B cells.
T-cell lymphomas show a high frequency of a characteristic chromosomal translocation, resulting in the combination of the NPM1/ALK genes and a fused oncogenic protein product.
Nephroblastoma (Wilms’ tumor) is the most common malignant kidney tumor in children. Mutations of the WT1 proto-oncogene are found in approximately 5 to 20 percent of Wilms’ tumors, half of which additionally carry mutations in CTNNB1, a proto-oncogene encoding beta-catenin.
Plasmacytomas frequently show chromosomal translocations, resulting in dysregulation of oncogenes followed by proliferation of a plasma cell clone. Genomic instability leads to further mutations and translocations.
The oncogene CCND1 product cyclin D1 is overexpressed in 34 to 81 percent of primary ductal mammary carcinomas, in part because of amplification of the region of the genome where the proto-oncogene is located. Other oncogenes that play roles in mammary carcinomas are HER2/neu (ERBB2), MYC (c-myc), and WNT1.
History: Oncogenes were first discovered in certain retroviruses and were later identified as cancer-causing agents in many animals. In 1976, it was demonstrated by J. Michael Bishop and Harold E. Varmus that cancer-causing genes (oncogenes) carried by certain viruses are derived from normal genes (proto-oncogenes) present in the cells of their host. Further research showed that such genes can cause cancer even without viral involvement.
Scientists have identified more than one hundred oncogenes in both animals and humans. Discoveries in the twenty-first century include the self-activating c-Src oncogene, RAS oncogenes, which have been indicated in 20 percent of human malignancies, and KRAS, found in pancreatic, colorectal, and lung cancers.
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