NAVIGATION


Lymphoma Research May Lead to New Therapies

Used with permission from the Purina Pro Club Boxer Update, Nestle Purina PetCare Company

New research findings showing that the prevalence of B-cell and T-cell lymphomas vary by dog breeds may eventually lead to new therapies for managing this cancer of the lymph nodes, which occurs more frequently in Boxers than many other breeds.

T-cell lymphocytes and B-cell lymphocytes are two subtypes of white blood cells. They are part of the normal immune system, but either cell type may undergo changes leading to the development of cancer known as lymphoma.

The research, which was published in the July 2005 issue of Cancer Research, showed "that in some breeds, there is an excess of T-cell lymphoma compared to the frequency in all other dog breeds, while in others, there is an excess of B-cell lymphoma," says Matthew Breen, Ph.D., associate professor of genomics at North Carolina State University and one of the research investigators. "We have identified that different types of canine cancer are associated with different chromosomal changes, which may be considered diagnostic of that particular cancer."

Working together Breen and Jaime Modiano, V.M.D., Ph.D., associate professor of immunology at the University of Colorado at Denver and Health Sciences Center, studied chromosomal and molecular changes that occur in dogs with lymphoma. Tapping into molecular cytogenetics, also known as fluorescence in situ hibridization (FISH), Breen and the scientists in his laboratory were able to observe numerical and structural chromosome abnormalities. These aberrations enable researchers to classify cancers into specific subtypes.

"In cancer, chromosomes -- nature's genetic filing cabinets -- become reorganized, resulting in bringing together genes that are not normally neighbors," Breen explains. "A gene in the wrong neighborhood can cause problems for control of the cell, which results in a cancer cell that may propagate and become a tumor."

Breed-Specific Abnormalities
Certain breeds of dogs have very specific chromosome aberrations and their susceptibility to develop cancer subtypes is assumed due to their genetic makeup. "The predisposition of certain breeds to develop lymphoma has been recognized for a long time, but this is the first indication that the tumors themselves harbor breed-specific genetic abnormalities," says Breen, noting he hopes the findings will lead to better understanding of why some subtypes of cancer respond better to therapy than others.

"Recurrent genetic abnormalities that occur with significantly higher frequency in a single breed can assist in the identification of candidate genes that are associated with the origin or progression of both canine and human cancers," Modiano says. This information may also be used to help identify corresponding genes that contribute to the risk of lymphoma in both species.

Researchers in the Modiano and Breen laboratories are focusing on molecular differences between lymphomas to determine the most effective chemotherapy for each kind of tumor. The Golden Retriever is being used as an index breed to compare to other breeds. Besides Boxer, other breeds that will be compared to this index breed include Rottweiler, Cocker Spaniel, Border Collie, Labrador Retriever, and Mastiff.

In addition, studies to determine risk where the scientists will produce linkage maps to compare haplotypes, or the genetic composition of individual chromosomes, of affected and unaffected animals from several breeds are in progress. "The goal is to associate a pattern of inheritance while correlating the genetic abnormalities of a tumor," Modiano says. "By looking at the DNA in chromosomes we can identify gene mutations that occur repeatedly, and determine how they affect the tumor growth rates and other characteristics about the cancer."

The information will be key in learning how tumors with different genetic abnormalities respond to therapy and may eventually help researchers to predict treatment expectations and to design new treatment protocols. Targeted therapy, which allows the use of toxic agents to cells based on structural or functional tumor characteristics, "is the wave of the future," Modiano says. "We're going to see it come to work and hopefully in an affordable manner."

The work is part of a large collaborative effort that involves scientists at five institutions. Besides Modiano and Breen, the other scientists are: Elaine Ostrander, Ph.D., of the National Human Genome Institute; Eric Lander, Ph.D., and Kerstin Lindblad-Toh, Ph.D., of the Genome Sequencing and Analysis program at the Broad Institute of MIT and Harvard; and William Kisseberth, D.V.M, DACVIM, and Cheryl London, D.V.M., Ph.D., DACVIM, of The Ohio State University.

Understanding Lymphoma
Lymphoma describes a tumor that grows in lymph nodes and arises from lymphocytes, or white blood cells that fight disease. The most noticeable signs are usually big masses around the neck, in front of the shoulders or behind the knees. Occasionally lymph nodes that are not visible or palpable from outside the body, such as inside the chest or abdomen, are affected.

Swollen nodes may cause other health problems. For example, large masses in a dog's neck may cause problems breathing or eating, and masses in the chest may make it hard to breathe so animals become tired or lethargic. Cancerous lymphocytes may also infiltrate certain organs of the body such as the gastrointestinal tract, spleen, liver or kidneys, leading to signs such as weight loss, vomiting, diarrhea or kidney failure. Malignant lymphocytes in bone marrow may cause a dog to become anemic and lethargic.

The lifetime risk of lymphoma in all breeds of dogs is estimated at approximately one in 15, yet the lifetime risk for Boxers is estimated at approximately one in four. Lymphoma is one of the five most common tumors seen in dogs, and it occurs about two to five times more frequently in dogs than in people. It accounts for 20 percent of all canine tumors, and four of five cancers originating from blood cells.

Though lymphoma can occur at any age, "it is most commonly seen in middle-aged to older dogs," Modiano says. "In the dog population, it peaks at about 10 or 11 years and at a slightly younger age in dogs from high-risk breeds. In older dogs, the incidence of lymphoma declines not because the risk is lower, but because there are fewer dogs. If the numbers were adjusted for age, then the risk would continue to be higher with increasing age."

However, it is worth noting that sometimes lymphoma even appears in puppies. Modiano says that the youngest dog he recalls being diagnosed with the cancer was 3 weeks old.

Managing Lymphoma
Veterinarians determine whether a dog has lymphoma by conducting a physical examination and taking a tissue biopsy. If lymphoma is diagnosed, it is important to learn how widespread the cancer is, which involves taking radiographs and/or performing an ultrasound, obtaining a blood sample for a complete blood count and blood biochemical profile, urinalysis, and a bone marrow sample. These tests help determine not only how widespread the cancer is but also help assess other important health parameters.

Some types of lymphoma progress rapidly, causing death in only one to two weeks, while other types develop more slowly and can go without treatment for years. Surgery is not recommended for managing lymphoma because the disease is not confined to a single site or organ.

Chemotherapy is the mainstay of treatment, although radiation therapy is being used experimentally in combination with chemotherapy and producing promising results, Modiano says. "Chemotherapy using one or two drugs generally results in remission, but this remission is relatively short-lived," he says. "More aggressive therapy using more drugs significantly improves a dog's chance for long-term survival. Better than 95 percent of treated dogs will achieve remission, meaning the disease will effectively disappear shortly after treatment."

With standard care, dogs survive on average 12 to 14 months. However, the intervals surrounding this average are quite large; some dogs can live for years, and others do not survive even one month, Modiano says.

"The length of remission also depends on the type of tumor," Modiano says. "In general, B-cell lymphomas respond better to treatment than T-cell lymphomas, but this is highly dependent on many other features of each tumor, and we see both very aggressive tumors and relatively indolent tumors that originate from both B cells and T cells."

Boxer Owners May Help to Advance Lymphoma Research
Owners of Boxers whose dogs have lymphoma can assist researchers by providing samples and financial assistance. For information, visit the Web site for the AKC Canine Health Foundation at www.akcchf.org.

If you are sending tissue samples, the laboratories ask for advance notice of at least 24 hours. For questions, you may send e-mails to info@modianolab.org or to CVM_K9Genomics@ncsu.edu.

Scientists at the Broad Institute of MIT and Harvard are seeking blood samples of dogs affected with B-cell lymphoma and healthy dogs 8 years of age and older. For information, go to www.broad.mit.edu/mammals/dogs, or you may contact Joanne Lai, the sample coordinator, at doginfo@broad.mit.edu.

At the National Human Genome Research Institute, researchers are interested in blood samples of dogs with T-cell lymphoma. For information contact Dana Mosher, the sample coordinator, at mosherd@mail.nih.gov.

All of the research institutes remind donors to be sure to check the box on the consent form that allows them to share samples with other scientists.

Breeding Dogs With Lymphoma
Breeders often want to know whether it is OK to breed a dog with lymphoma. Modiano advises that dogs with lymphoma probably should not be bred because the disease can be debilitating and because treatment can affect the genetic composition of eggs and sperm.

"Breeding is an energy-intensive process and a female with any systemic disease probably should not be bred," he says. "On the other hand, I wouldn't recommend against breeding healthy siblings of a dog that had lymphoma unless it is clear that the line or family had a higher incidence of lymphoma than the breed as a whole.

"We still do not understand the heritable factors that account for cancer risk, so it is difficult to make specific recommendations of how to develop a strategy to reduce cancer risk when selecting breeding stock," Modiano says. When breeders ask him whether they should breed a dog from a family with a history of lymphoma, he asks whether they would repeat the experience of sharing their life with the dog(s), even considering the cancer risk or experience. "If they say 'yes' that makes their decision easier," Modiano says.

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