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Cancer Biology and Pathogenesis

why and how do we approach the study of cancer using comparative approaches?

Cancer is the leading cause of death in humans under the age of 85, as well as the leading cause of disease-related death in dogs. As such, it has gained exceptional importance in our society. Both genetic and environmental factors have major effects on the temporal occurrence of cancer, and there is thus a new emphasis to learn more about how these factors influence cellular and molecular changes in cancer. Dogs and people are susceptible to many of the same types of cancer and the natural history (incidence, age of onset, location, progression, outcome) of many cancer types is similar in both species. Our pet dogs share our environment closely, allowing us to examine not only the heritable risk factors, but also those associated with the environment. Moreover, when compared to humans, dogs have shorter generational life spans (as many as five or more related generations frequently co-exist), extended pedigrees with detailed family histories, and more homogeneous genetic backgrounds, which provide unique opportunities to address questions about the origin and behavior of cancer. The answers we obtain studying cancers of dogs will contribute to our ultimate goals to design strategies for prevention and treatment of cancer in both dogs and people.

To understand the implications of cancer, one must first realize that cancer is not a simple disease. Rather, the term cancer describes a large number of diseases whose only common feature is uncontrolled cell growth and proliferation. A very important concept that is now universally accepted is that “cancer is a genetic disease, although it is not always heritable.” Tumors arise from cells that accumulate mutations which eliminate normal constraints of proliferation and genetic integrity. These mutations provide cells a selective growth advantage within their environment. This is essentially the same evolutionary phenomenon that we call “natural selection”, albeit on a microscopic scale. Various theories have been proposed to explain the genetic basis of cancer. One explanation invokes stochastic (random) events – the inherent error rate of enzymes that control DNA replication during each division introduces about 1 in 1,000,000 to 1 in 10,000,000 mutations for each base that is replicated during each round of replication. The genome consists of many millions of base pairs, so each daughter cell is likely to carry at least a few mutations in its DNA. Most of these mutations are silent; that is, they do not present any problems to 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. An alternative hypothesis is that mutations are not stochastic, but rather “directed” due to the presence of a “mutator phenotype,” where the factors that control DNA replication and repair are inherently prone to more errors than would be expected by simple stochastic events in particular individuals. This leads to different cancer predispositions, which would be higher than the mean in such individuals, and might explain why not all people (or dogs) exposed to similar environmental carcinogens develop the same forms cancer at the same rate. There is strong evidence to support both mechanisms (stochastic and directed) in people and animals.

Focus on Canine Cancer
For this program, we seek to define peculiar genetic traits that are the cause of cancer in dogs (and by extension, humans). Mutations of specific genes that increase the probability, or risk, that an individual (actually a cell) will develop a tumor. In most cases (estimated to be >95%), these mutations occur “sporadically”, that is, they alter the DNA of non-reproductive (somatic) cells. These mutations arise in susceptible individuals upon exposure to certain environmental insults, although the risk is not necessarily shared by relatives of the affected individual. Nevertheless, identifying the patterns of mutations associated with specific tumor types is likely to provide information to obtain a more accurate prognosis, and to develop more effective treatments.

On the other hand, in those rare cases where mutations occur in reproductive cells, they are passed on in the germ line. Identification of such mutations should help us predict relative cancer risk in individuals (or the likelihood of individuals to produce progeny with elevated cancer risks), allowing us to invest in practices to modify the environment that may reduce or eliminate the risk (cancer prevention). The investigation of cancer susceptibility in families or breeds of dogs is of critical importance to dog breeders and dog owners alike. Unlike other heritable conditions, genetic susceptibility to cancer may not manifest in disease until a dog has reached middle age, and long after it has achieved breeding potential. When present, this genetic susceptibility may be due to a process called loss of heterozygosity. Individuals inherit two copies of each gene upon conception, one from the sire, and one from the dam. Each of these gene copies is called an “allele.” A family or breed may have through the course of time, lost a functional allele of a “tumor suppressor gene” through mutation. The affected individuals are heterozygous (that is, they have two different alleles, and only one is functional). These individuals may not develop disease (cancer), unless the second, functional copy of the gene in question is mutated in a cell that retains the capacity to divide. Even in the best of circumstances, genetic analysis can only predict the probability or provide a relative risk, rather than a definitive assessment of whether or not the individual will in fact develop cancer.