Health Issues Cancer

Dogs, Genes, and Cancer:
Why Cancer Happens and What We Can Do to Prevent and Treat It.

Due to advances in veterinary health care, dogs are living to older age when most cancer types occur
with greater incidence. Cancer is now the leading cause of disease-related death in dogs, and as such, it
has gained exceptional importance in our society. Genetic and environmental factors also have major
effects on the temporal occurrence of cancer and are the basis of research on what causes cancer
(pathogenesis), as well as prevention, diagnosis and treatment. Thus, a new emphasis has developed to
learn more about genetic and environmental factors that influence cellular and molecular changes in canine
cancer. Dogs and people are susceptible to many of the same types of cancer and the natural history of
many cancer types appear to be similar in both species. The shorter life span of dogs (both in terms of
life-years and generations) and the availability of extended pedigrees with detailed family histories,
provide a unique opportunity to address causative issues of cancer that will be important for both dogs
and people. Cancer is a genetic disease. The term cancer refers to a large number of diseases whose
common feature is uncontrolled cell growth and proliferation (multiplication). This loss of cell growth
control results from an accumulation of mutations (errors introduced into the DNA code) in genes that
control cell division and cell survival. The most common mechanism that introduces mutations into the
DNA of somatic cells (non-reproductive cells) is the inherent error that occurs during normal cell
division. In mammalian cells, there is an error rate of about 1 in 1,000,000 to 1 in 10,000,000 bases
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 suppresser genes or activate oncogenes that respectively inhibit or promote cell division and
survival. A cell that accumulates sufficient mutations which eliminate steps necessary to restrain
proliferation and maintain genetic integrity can give rise to a tumor. Because of the mutations, this cell
and its progeny acquire a selective growth advantage within their environment. This is essentially the
same phenomenon that we call natural selection, albeit on a microscopic scale. Given the fact that cell
division is responsible for most mutations, it is not surprising that the most common cancers arise from
cells that divide frequently in the performance of their function. The origin of these cancers, then, is
genetic because it lies in the malfunction of genes that control growth and survival, but these cancers are
considered to be sporadic (that is, they are largely independent of heritable risk factors).Cancer risk
can be inherited. Mutations that contribute to cancer can also be inherited. An inherited mutation in a
single gene that is important in cell growth control will increase the risk of that individual to develop
cancer. This can be due to reducing the overall number of acquired mutations that must accumulate
before a cell becomes cancerous, or it can be due to disabling a critical safeguard gene that normally
prevents cells from becoming tumors. In humans, it is estimated that approximately 5% of cancers occur in
people who have known heritable risk factors. In dogs, there appears to be a predisposition among
certain breeds or families to develop specific types of cancer, suggesting that a hereditary component
may be important in the development or progression of the disease. However, the existence of heritable
cancer syndromes in dogs remains to be conclusively proven. How is cancer kept at bay? Although both
heritable factors and behavioral factors are known that increase the risk of cancer in people, similar
information for dogs is limited. We know, for example, that neutering has a protective effect on hormone
related cancers (mammary cancer and prostate cancer) and this information has been used extensively to
reduce the prevalence of these tumors in the non-breeding population of pet dogs. But little is known
regarding specific factors that influence the risks for other cancers. Nevertheless, it is fortunate that
dogs (like other higher vertebrates) have developed many built-in safeguards which mandate that
abnormal cells be destroyed. For that reason, before cancer can take hold, a malignant cell must
eliminate or evade these safeguards. Despite the alarming incidence of cancer in older dogs, the
reliability of these systems is evident in the fact that many of our pets do not develop cancer until they
reach an advanced age if at all. Lymphoma (cancer of the lymph glands) and osteosarcoma (bone cancer)
are among the tumors that are commonly seen in dogs. Lymphoma accounts for approximately 20% of all
canine tumors, and >80% of cancers originating from blood cells. Most of the time, lymphoma appears
as swollen glands (lymph nodes) that can be seen or felt under the neck, in front of the shoulders, or
behind the knee. Occasionally, lymphoma can affect lymph nodes that are not visible or palpable from
outside the body, such as those inside the chest or in the abdomen. In these cases, dogs may accumulate
fluid in the chest that makes breathing difficult, or they may have digestive problems (diarrhea, vomiting,
or painful abdomen). If left untreated, dogs with lymphoma will generally succumb to the disease within 3
to 4 weeks. Treatment with prednisone (a corticosteroid) alone generally can induce rapid, but
short-lived remissions (usually less than 6 to 8 weeks), and frequently renders the disease resistant to
further treatment. Durable remissions are achievable in lymphoma, so the disease is generally considered
to be treatable. Multi-agent chemotherapy, which is the standard of care for this disease, will induce
remissions of 12 to 18 months in many cases. However, there are various subtypes of lymphoma that
exhibit different behaviors, and some of the more aggressive types are unresponsive to any available
treatment. For example, the median survival for dogs with lymphoma originating from B cells treated with
multi-agent chemotherapy is approximately 14 months, whereas the median survival for dogs with
lymphoma originating from T cells treated with multi-agent chemotherapy is approximately 6 months.
However, there remains a lot of variability in the responses seen even when tumors are classified into
these subtypes. Osteosarcoma accounts for 85% of skeletal cancers. Large and giant breed dogs are
at highest risk for developing osteosarcoma, possibly due to the fact that bone cells at the growth
plates must divide many times to create the very long bones that are characteristic in these breeds.
However, there probably are additional risk factors, which have yet to be defined. Osteosarcomas
generally occur in the limbs, however, these tumors can arise anywhere in the long bones, as well as in flat
bones (ribs, skull, and spine). Osteosarcoma is always a life-threatening disease because it is highly
metastatic, making treatment of this type of cancer especially difficult. The standard of care for
osteosarcoma of the limbs includes amputation or limb-sparing surgery, followed by adjuvant
chemotherapy. The median survival for dogs with osteosarcoma treated with surgery alone is
approximately 100 days. The addition of chemotherapy (usually doxorubicin or a platinum drug) to the
treatment regimen increases the median survival to >300 days. Various factors can be used to predict
response to therapy, including the anatomic location and size of the tumor and serum alkaline
phosphatase concentrations. However, there are no truly robust predictors of response, and the
survival of dogs with osteosarcoma treated with standard of care can range from weeks to years. What
can we do to prevent and treat cancer? There are several breed clubs and animal health organizations,
including the AKC Canine Health Foundation and the MCOA that are supporting research projects
that will help define cancer risk factors for dogs, and also to develop rational new treatment strategies
to improve the outcome of cancer patients. The AKC Canine Health Foundation recently launched a
Cancer Initiative to raise almost one million dollars to support cancer research projects. These
projects seek to define markers of heritable cancer risk, identify markers that improve the ability of
veterinarians to predict responses to standard, available treatments, and develop new strategies for
therapy based on known genetic anomalies peculiar to tumors. The research project "Heritable
and Sporadic Genetic Lesions in Canine Lymphoma and Osteosarcoma" (AKC CHF Grant
2254), which is supported in part by the MCOA, is a collaborative effort between Dr. Jaime Modiano
at the AMC Cancer Research Center in Denver, CO and Dr. Matthew Breen at North Carolina
State University in Raleigh, NC that seeks to determine how genes impact the development of cancer
in dogs. Specifically, the researchers will study abnormalities in genes and chromosomes in lymphoma and
osteosarcoma to determine if these abnormalities are inherited, and to assess their clinical significance
(that is, if they are predictive regarding response to treatment and prognosis). In the short term (few
years), this study may help identify genetic pawprints in tumors that can be used to predict if they are
likely to respond to conventional therapy, allowing owners of affected dogs to make more informed
decisions regarding treatment for their pets. In the long term, we anticipate that this and other studies
may define specific gene markers that define cancer risk for individuals and their progeny that can be
used for judicious breeding decisions to reduce the incidence of cancer in dogs.