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5.1 INTRODUCTION

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There is overwhelming evidence that mutations can cause cancer. Major evidence for the genetic origin of cancer includes: (a) the observation of Ames (Ames et al, 1981) that many carcinogens are also mutagens, and (b), the finding that genetically determined traits associated with a deficiency in the enzymes necessary to repair lesions in DNA are associated with an increased risk of cancer. Mutations may occur in the germline of an individual and be represented in every cell in the body, or they may occur in a single somatic cell and be identified in a tumor following clonal proliferation. As described in Chapter 6, all species have numerous genes called cellular oncogenes (or protooncogenes), many of which are homologous to the transforming oncogenes carried by specific RNA retroviruses. Some human tumors have mutations in these oncogenes that may have led to their activation. However, there is no evidence for germline mutations in cellular oncogenes, perhaps because such mutations in the germline are lethal even in the heterozygous state. In contrast, there is good evidence for germline mutations affecting tumor-suppressor genes, which can lead to familial clustering of cancer or transmission of predisposition to tumors. In such cases, the loss-of-function of a tumor-suppressor gene is inherited in a mendelian manner.

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The maintenance of genetic information is of paramount importance for prevention of genetic instability and accompanying carcinogenesis. In this chapter, intrinsic and extrinsic causes of genomic instability are discussed and the biochemical pathways that act to repair specific DNA lesions and the function of cell-cycle checkpoints following DNA damage are described. The methods used to evaluate DNA damage sensing and repair are detailed and human disorders that result in defective DNA damage sensing and repair are discussed. Finally, the importance of the appropriate maintenance of chromosomal length and telomerase activity is highlighted. Throughout the chapter, examples are given of the importance of each of these factors in the genesis, diagnosis, and treatment of human cancer.

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5.2 GENETIC INSTABILITY AS THE BASIS FOR MALIGNANT TRANSFORMATION

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5.2.1 Intrinsic Causes of Genetic Instability

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Cellular carcinogenesis is known to require sequential mutations in DNA (see Chap. 4, Sec. 4.2.3). Damaged DNA is produced by a number of mechanisms, including (a) spontaneous reactions of DNA with the aqueous environment, (b) influence of metabolic byproducts such as reactive oxygen or nitrogen species, (c) action of environmental mutagens such as radon and chemical exposures, and (d) errors during DNA replication. Together these mechanisms can produce abasic sites, deamination, base alterations, single-strand DNA breaks and double-strand DNA breaks, which can amount to as many as 105 DNA lesions per cell per day (Ciccia and Elledge, 2010; Hoeijmakers, 2009). Unless the cell can protect and maintain the integrity of the genome, these genetic alterations may cause cancer by activating protooncogenes and/or inactivating tumor-suppressor genes. Natural mutation rates appear sufficient to drive the ...

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