Jerold S. Bell, DVM
Fifty percent of elderly dogs develop some form of cancer. Specialists are finding that certain cancers are developing earlier in life than cancer had usually developed, and that some breeds have a higher risk for developing specific types of cancer. Hereditary cancers do tend to develop earlier in life. All of this has led researchers to question breed-related cancer risk and the genetic mechanisms that cause cancer.
Cancer can be generally defined as abnormal and malignant cell division and maturation. The uncontrolled division of undifferentiated cells forms tumors. Normal cell division occurs through the genetic process called mitosis. The transformation from a normal cell into a cancerous cell involves the turning on or off of normal genetic instructions.
Although genes are involved in the development of cancer, most cancers are thought to be nonhereditary. Most types of cancers occur spontaneously, due either to mistakes in the constantly dividing cells of the body or to mutations triggered by environmental forces (such as radiation, toxins, and viruses). If these mutations occur in cells other than those that produce sperm or eggs, then a cancer liability is not going to be passed from one generation to the next.
There are certain cancers that we do consider to be hereditary, due to a significantly higher incidence in specific breeds or families. In some instances, usually involving breeds that have a high incidence of cancer, the mutation occurred many generations ago. When a cancer liability appears to be limited to a particular family, however, the mutation may have occurred fairly recently.
Cancer Causing Genes
Among all species, approximately 100 genes that have the potential to cause cancer-that is, genes that control cell division-have been identified. In the normal state, some of these genes, the ones called tumor-suppressor genes, prevent the undifferentiated replication of cells.
Most tumor-suppressor genes only require that one of the gene pair be normal to prevent cancerous growth. If a dog inherits one normal copy, and one mutated copy, the dog will be at higher risk for developing tumors. It will only take a single mutation in the normal gene to promote the production of cancer cells. Such defective genes can be screened for as "cancer susceptibility genes." If a dog inherits two normal genes, a spontaneous mutation must occur in both to promote cancer. This is a less likely scenario.
Studies have shown that inherited mutations of the tumor-suppressor gene p53 are found in many canine cancers. For example, this gene can be found in some, though not all, families that have hereditary breast cancer. The tumor-suppressor gene waf-1 has been implicated in canine families with melanoma and osteosarcoma, while the gene PTEN is being studied in hemangiosarcoma and osteosarcoma.
Oncogenes are another type of cancer-causing gene. These initiate a process of undifferentiated cell growth. Oncogenes can act either recessively or in a dominant fashion. In the latter case, a mutation in a single oncogene can cause cancer cells to develop.
Proto-oncogenes can stimulate cancer by affecting cellular growth factors and growth factor receptors. The proto-oncogene called c-kit has been implicated in mast cell tumors, the most common type of malignant tumor in dogs.
The AKC Canine Health Foundation sponsored a scientific symposium on Canine Cancer Genetics in May 2001. Several research scientists summarized the current knowledge concerning cancer in dogs.
Dr. Lawrence Loeb from the University of Washington, the keynote speaker, discussed the body's DNA repair mechanisms. With millions of cells dividing in the body every day, there are a great many spontaneous DNA "mistakes" or mutations that occur. DNA-repair genes constantly monitor cellular DNA for these mistakes, preventing them from spreading.
Dr. Loeb reported that mutations in DNA-repair genes (a type of tumor-suppressor gene) could cause cells to become cancerous, constantly dividing and forming tumors. He also reported that the onset of cancer can be due to an accumulation of separate mutations that, over time, combine to allow the growth of tumor cells. It has also been shown that as tumor cells divide, they mutate more rapidly than normal cells, indicating a loss of DNA-repair genes.
Dr. Terri King, a statistical geneticist from the University of Texas at Houston, discussed the findings of studies on inherited cancers in dogs. Large-bodied breeds of dogs have twice the cancer incidence of smaller-sized breeds. Dr. King cited breed-related cancer risk based on accumulated case reports. Osteosarcoma was most prevalent in Great Danes, Saint Bernards, Doberman Pinchers, and Labradors. Skin and soft-tissue cancers were most prevalent in Saint Bernards, Bassett Hounds, German Shepherds, Golden Retrievers, English Setters, Great Danes, Pointers, and Flat-Coated Retrievers. Breast tumors were most prevalent in Pointers, Poodles, Pulik, Cocker Spaniels, German Shorthaired Pointers, and Boston Terriers. Melanomas were most prevalent in Scottish Terriers, German Shorthaired Pointers, Cocker Spaniels, Pointers, Weirmeraners, Golden Retrievers, and Boxers. An overall reduced cancer risk was found in Dachshunds and Beagles.
A number of research studies of hereditary canine cancers have been recently completed or are under way. Dr. King studied cancer in Flat-Coated Retrievers. She found that many dogs in the overall breed population had been diagnosed with tumors of a variety of types, with a peak in incidence at 7½ years of age. In the subset of Flat-Coated Retrievers that were diagnosed with malignant fiberous histiocytomas, the peak occurred at 3½ years of age. This suggests a hereditary risk of this cancer in the breed.
Dr. Elaine Ostrander of the Fred Hutchinson Cancer Research Center, working with several researchers from Norway identified a linked marker for inherited kidney cancer (renal cystadenoma) in German Shepherd Dogs. The pattern of inheritance indicates an autosomal dominant mode of inheritance.
Dr. George Padgett, of Michigan State University and others have determined that malignant histiocytosis is a polygenically inherited disorder in Bernese Mountain Dogs.
Dr. Ann Jeglum of Veterinary Oncology Services and the Wistar Institute, has been studying familial lymphoma in Golden Retrievers. The study's goal is to determine whether the many cases of this cancer in the breed suggests that it is hereditary or whether it seems that way because the breed is so populous.
Dr. Elizabeth McNiel and others at Colorado State University have been researching the high incidence of stomach cancer in Chow Chows.
Dr. Jaime Modiano of the AMC Cancer Research Center has been studying the significance of tumor-suppressor genes in lymphoma and melanoma.
You can find more information on some of these studies, and others currently being funded by the AKC/CHF, by visiting the Web site at www.akcchf.org, or by calling 882-682-9696.
There is still a lot that we don't know about hereditary aspects of canine cancer. Several cancer susceptibility genes have been identified, but they are not specific for types of cancer. Many breeds have a higher incidence of specific cancers, but we do not know how this risk is inherited. The progress that is being made with the canine-genome map, along with the cooperation of breeders and breed clubs, should provide us with answers. This will include tests for cancer susceptibility, as well as new methods for the treatment of cancer.
(This article originally appeared in the "Healthy Dog" section of the January, 2002 AKC Gazette)