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CANCER GENES

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Over the past 50 years, multiple discoveries have had an impact on our understanding of key genomic events that influence the development of malignant growth. After many large-scale sequencing projects of cancer genomes, we now understand that many genetic alterations in specific cancer genes are responsible for the development and progression of the disease. These alterations may occur at the level of the patient’s germline, predisposing to inherited forms of cancer that may develop in many tissues throughout the body. Genetic alterations may also be somatic, or newly acquired changes within the genes of an individual cell or group of cells over time and due to environmental stresses. Somatic alterations may come in many forms, including single-base substitutions; insertions or deletions of DNA fragments; rearrangements and rejoining of DNA from alternative locations in the genome; and copy number increases and reductions. Should these alterations effect key cancer genes, malignancy may develop.

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In the early 1970s, when studying retroviruses that reverse transcribe RNA into DNA, it was found that (1) certain retroviruses, when incorporated into host cells, have the ability to transform normal cells into rapidly dividing tumors. Rous sarcoma virus (RSV), isolated by Peyton Rous, was the first retrovirus found to cause sarcoma in chickens (2). Later, hybridization studies proved that the RSV gene, termed v-src, was homologous to a highly conserved eukaryotic gene, c-src. Src became the first known viral oncogene (3). In contrast to highly transforming retroviruses, weakly transforming viruses can insert into the genome near proto-oncogenes, normal genes that when mutated give rise to an oncogene, and induce cancer. Activation of proto-oncogenes to oncogenes, through activating point mutations, gene amplification, or chromosomal translocation events, can occur independent of retroviral transformation and cause cancer.

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In 1981, Shih and colleagues showed that normal NIH3T3 mouse fibroblast cells could be made cancerous by introduction of total genomic DNA from human cancers (4). Isolation of the specific DNA segment responsible for this transforming activity led to the identification of the first naturally occurring, human cancer-causing sequence change—the single-base G > T substitution that causes a glycine-to-valine substitution in codon 12 of the HRAS gene (5). These experiments demonstrated the causal relationship between oncogenic mutations and cancer. The discovery of HRAS and many other oncogenes altered our understanding of cancer and expanded our knowledge of driver mutations that can be targeted to treat disease.

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Another commonly referred to class of cancer genes is tumor suppressor genes. These genes are frequently involved in cell cycle regulation, inhibition of cellular proliferation, and DNA repair. When functioning normally, they act as barriers to unregulated tumor growth. However, dysfunction of both copies of the gene are usually required to initiate tumor development as only one functioning copy is needed to regulate the cell. Alfred Knudson, in 1971, was the first to theorize about the role of tumor ...

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