Genetics of Canine Cancer Jaime F. Modiano, PhD  Center for Cancer Causation and Prevention, AMC Cancer Research Center

Summary:

The term cancer refers to a large number of diseases whose only common feature is uncontrolled cell growth and proliferation. Cancer can affect any dog of any breed at any age; however, there appears to be a predisposition among certain breeds or families of dogs to develop specific types of cancer. Among these, lymphoma and leukemia (cancers of white blood cells) seem to be especially common in Golden Retrievers and Boxers, melanoma (cancer of pigmented cells responsible for skin coloring) is seen often in Irish and Gordon Setters, Standard and Miniature Schnauzers, Doberman Pinschers, and Scottish Terriers, and osteosarcoma (cancer of the bone) occurs commonly in Rottweilers and many other giant breeds. The clustering of specific cancers in breeds and families suggests that a hereditary component may be important in the development or progression of the disease.

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 is most likely to be due to a process called loss of heterozygosity. Individuals inherit 2 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 a 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 will not develop disease (cancer), unless the second, functional copy of the "tumor suppressor gene" in question is mutated in a cell that retains the capacity to divide; for example, white blood cells that undergo division as they fight infections, pigment-producing cells that divide as a response to insult or injury to the skin, or bone cells that undergo division in the process of bone remodeling.

Tumor suppressor genes encode proteins that prevent or retard cell division. Tumor suppressor genes will even constrain or eliminate renegade cells that have initiated the path to cancer; thus mutations that disable these genes contribute to the development and progression of cancer. Tumor suppressor genes can be grouped in 3 broad categories. One group of tumor suppressor genes that includes p53 and ATM among others, is responsible for controlling DNA repair. Cells can undergo spontaneous mutations, and these tumor suppressor genes must ensure that the mutant cells do not divide until the errors in their DNA sequence are repaired. Another group of tumor suppressor genes controls cellular aging or senescence. These genes encode proteins such as the cyclin-dependent kinase inhibitor p16/Mts-1. Each cell in the body has the potential for a finite number of divisions, and these genes prevent further replication when that number has been reached. The third group of tumor suppressor genes serves to counteract the function of growth-promoting genes. Among these are RB, the cyclin-dependent kinase inhibitor p21I /Waf-1 and PTEN. In the examples above, tumor suppressor genes would be activated as it became necessary to terminate an immune response, at the end of the healing process of the skin, and when bone remodeling was complete.

Loss of the growth control pathways regulated by various tumor suppressor proteins such as those listed above is associated with the origin and progression of lymphoma, leukemia, melanoma, and osteosarcoma in humans and laboratory animals. Moreover, cancers that arise due to other mutations but that retain the expression of certain tumor suppressor genes such as p16/Mts-1 and p21/Waf-1 have been shown to respond more favorably to therapy, making these promising targets for genetic therapy of cancer.

Our laboratory has characterized some of the mechanisms that control tumor suppressor gene function in canine cells. For these project, we have cloned the canine homologues of p16/Mts-1 and p21/Waf-1. Additionally, in collaboration with the laboratory of Dr. D. Shippen we have cloned the genomic sequence for canine telomerase, another important gene that is important in cellular aging and cancer. We now plan to examine the frequency of mutations of these genes in canine lymphoma, melanoma, and osteosarcoma in families of Doberman Pinschers, Golden Retrievers, Boxers, and Rottweilers with high cancer prevalence. This will enable us to determine the relationship of tumor suppressor gene mutations with the prevalence of lymphoma, melanoma, and osteosarcoma in these high-risk breeds, as well as with prognosis and outcome. The results from our studies will provide tools that may predict the risk of a dog or its offspring to develop these devastating tumors. This information could have an immediate, visible, and long-lasting impact on canine health when used judiciously for breeding decisions. Additionally, it may be useful in the future to pave the way towards the development of advanced molecular therapies for canine cancer.

Dr. Modiano's work is supported by the following grant from the AKC Canine Health Foundation:

No. 1626: Significance of Tumor Suppressor Genes in Canine Cancer (Sponsored in part by the American Boxer Charitable Trust, Doberman Pinscher Foundation of America, Golden Retriever Club of America in Honor of Carol Buckman, and the Medallion Rottweiler Club)

Biographical Profile

Dr. Jaime Modiano completed his veterinary training and PhD in Immunology at the University of Pennsylvania, a residency in Veterinary Clinical Pathology at Colorado State University, and a post-doctoral fellowship at the National Jewish Center for Immunology and Respiratory Medicine. He was appointed to the faculty in the Department of Veterinary Pathobiology at Texas A&M University as Assistant Professor between 1995 and 1999. Currently, Dr. Modiano is a scientist in the Center for Cancer Causation and Prevention at the AMC Cancer Research Center in Denver, CO, and a Full Member of the Comprehensive Cancer Center of the University of Colorado Health Sciences Center. His research program is supported through federal and private sources. Dr. Modiano has co-authored more than 25 peer-reviewed scientific manuscripts, and over 50 abstracts, presentations, and book chapters focused on various aspects of cancer biology, including the genetic basis of cancer and applications of genetic immunotherapy to treat metastatic tumors. Dr. Modiano is married to Dr. Michelle G. Ritt, a board certified specialist in Veterinary Internal Medicine. They share their home with 2 dogs ("Doc", a Gordon Setter and "Kira", a "Malamutt") and I tabby cat ("Basho").