Download PDF Withrow & MacEwen’s Small Animal Clinical Oncology 5th edition by Stephen J. Withrow

Sinopsis

This is an exciting and rapidly evolving time in the field of cancer genetics. Although it has been clear for several decades that cancer is a disease driven by the accumulation of genetic abnormalities,1,2 new technologies are rapidly unraveling nuances in how heritable traits influence epigenetics and the tumor environment. Meticulous reductionist research done since the early 1960s helped identify hundreds of genetic abnormalities that are peculiarly associated with specific cancers, and more recent advances allowed for full sequencing of tumor genomes.3-6 The information from these experiments has reinforced current concepts and provided insight into new areas of research. This chapter will focus on contemporary information to provide context for the genetic basis of cancer and how interactions between genes and environment impact the origin, progression, and response to therapy of hematopoietic tumors. It is probably reasonable to say that the next decade will represent a new “golden age” of discovery in cancer genetics, when many of the apparent conflicts from our traditional (reductionist) experimental approaches will be resolved by integration of data from epidemiologic, molecular, and clinical studies into a more holistic understanding of the biology of cancer.

To understand cancer, one must first realize that cancer is neither a single nor a simple disease. Rather, the term cancer describes a large number of diseases whose only common feature is uncontrolled cell growth and proliferation. An important concept that is universally accepted is that cancer is a genetic disease, although it is not always heritable. Tumors arise from the accumulation of mutations that eliminate normal constraints of proliferation and genetic integrity in a somatic cell. Among other causes, mutations can arise following exposure to environmental mutagens such as cigarette smoke, ultraviolet irradiation, and others. In fact, changes in cancer incidence over the course of the twentieth century, many reflecting behavior patterns (e.g., lung cancer in smokers), infectious diseases (e.g., stomach cancer in people infected with Helicobacter pylori), or exposure to special cultural factors such as urbanization or diet (e.g., increasing breast cancer rates in the second and subsequent generations of Asian-American women), underscore the significant influence that the environment exerts on the genetic make-up of any individual. Nevertheless, it would be incorrect to assume that the environment is wholly responsible for most tumors; most associations of cancer and exposure to potential environmental carcinogens other than tobacco products and ultraviolet or gamma irradiation are relatively weak.

Rigorous experimental evidence now supports a number of “intrinsic mutagens” that interact in complex and sometimes unpredictable ways with environmental triggers to promote cancer. For example, it is clear now that oxygen free radicals that result from chronic inflammation can act as procarcinogenic mutagens. An equally important and perhaps less well-recognized “mutagen” is the inherent error rate of enzymes that control DNA replication, which introduces from 1 in 10,000,000 to 1 in 1,000,000 mutations for each base that is replicated during each round of cell division. Most mammalian genomes comprise 2 to 3 billion base pairs, so every time a cell divides, each daughter cell is likely to carry at least a few hundred mutations in its DNA. Most mutations, whether caused by extrinsic or intrinsic factors, are silent; that is, they do not hinder the cell’s ability to function. However, others can disable tumor suppressor genes or activate proto-oncogenes that respectively inhibit or promote cell division and survival. Thus it can be said that “being alive” is the single largest risk factor for cancer.

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