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KNAPP, DHAWAN, AND OSTRANDER
in dogs can help identify not yet known exposures that have
the potential to contribute to understanding of human
cancer. 20-22 The compressed life span of dogs compared with
humans facilitates cancer prevention research in that a 15 to
20 year period in human life can be studied in dogs in 2 to 3
years. In an intriguing example, a 7-month study in older
dogs (physiologically equivalent to human age 62 to 69) demonstrated
a U-shaped dose-response relationship between
selenium status (toenail selenium concentration) and provided
target concentrations to prevent DNA damage and
induce apoptosis within the prostate. 23-24 Midrange concentrations
were associated with protective effects, whereas
DNA damage was most pronounced at the lowest and highest
selenium concentrations along the curve. This study offered
a possible explanation for the failure of the 7-year
Selenium and Vitamin E Cancer Prevention Trial (SELECT)
of 35,000 men, which had begun before the dog study; the
concentrations achieved in men in the SELECT study were
not in the benefıcial range as defıned by the dog study.
Study Opportunities Afforded by Strong
Breed-Associated Risk for Cancer in Dogs
Another intriguing aspect of cancer research in pet dogs is
the tremendous opportunities offered by strong breedassociated
risk for certain types of cancer. Examples include
the 23-fold increased risk for squamous cell carcinoma of the
digit in Giant Schnauzers 9 and the 21-fold increased risk for
invasive bladder cancer in Scottish Terriers 8 compared with
mixed breed dogs. These fındings, along with the sequencing
of the dog genome, 25 offer unparalleled opportunities to uncover
complex traits leading to cancer development, including
gene-gene and gene-environment analyses. For a specifıc
cancer type, the number of deleterious alleles segregating in a
single dog breed is expected to be limited because of essentially
closed breeding in the establishment and maintenance
of the breed. 9 Dog breeds are genetically far more simple
compared with dog or human populations as a whole. 26 This
KEY POINTS
There is a crucial need for advances in cancer prevention,
and research in relevant animal models is key.
Of the over 80 million pet dogs in the United States, a
quarter are expected to die from cancer.
Specific forms of naturally occurring cancer in pet dogs,
including invasive urinary bladder cancer, closely mimic the
human condition.
Breed-associated risks for cancer in pet dogs offer
unparalleled opportunities to define genetic factors, genegene
interactions, and gene-environment interactions that
lead to cancer across species.
Clinical studies in dogs are considered win-win-win
opportunities in which the individual dog benefits, and
knowledge is gained that can improve the outlook for dogs
and humans facing cancer.
allows researchers to circumvent small family size, outbred
population structure, and locus heterogeneity that limit human
cancer gene mapping. 27.28 Detailed records of dog
breeding by breed clubs add to the value of the model. 9 When
taking advantage of breed-associated cancer risk, including
genome wide association studies (GWAS), analyses can be
performed with much fewer subjects than would be required
for a human GWAS study. For example, an initial GWAS
performed on 31 Standard Poodle cases and 34 controls allowed
identifıcation of a locus on canine chromosome 15 for
squamous cell carcinoma of the digit with high signifıcance
that spanned approximately 1 million base pairs. Additional
mapping and sequencing with less than 100 additional dogs
revealed a founder mutation—a copy number variant affecting
KITL expression. 9,29 The expectation is that there are
shared genetic factors that drive cancer development in both
dogs and humans; however, many of these factors are diffıcult
to elucidate in humans, but dog studies can allow the
identifıcation and understanding of complex traits important
in human cancer.
One example of this involves mutations leading to a renal
cancer syndrome in German Shepherd Dogs that mimics
that in Birt-Hogg-Dubé syndrome in people. 30 The locus was
initially found using one large family, characterized by a single
male that had been crossed to a number of females. Analysis
of the progeny of the crosses allowed the locus to be
reduced to a small size, and the underlying causative gene,
folliculin, to be identifıed. Of note, the locus was mapped fırst
in dogs, then in humans. Yet mutations in the same gene produce
very similar cancer syndromes in humans and dogs.
NEEDS AND OPPORTUNITIES IN INVASIVE BLADDER
CANCER RESEARCH
Current Challenges in Human Invasive Bladder Cancer
One of the best examples of a canine cancer with high translational
potential and value is invasive urinary bladder cancer,
specifıcally iUC, also referred to as invasive transitional
cell carcinoma. There is a clear need to improve the outlook
for people who have or who are at risk for developing this
cancer. More than 16,000 people in the United States 31 and
over 160,000 people worldwide 32 die from iUC each year.
Clinical consequences include urinary obstruction as a result
of progression of the primary tumor and major organ failure
from metastasis. Both can cause substantial morbidity and
lead to death. The mainstay of front-line treatment for
bladder-confıned iUC is cystectomy. 33 Many patients, however,
are not candidates for this involved surgery because of
comorbid conditions. Of those who undergo surgery, approximately
50% develop distant metastases. 34 Despite initial
favorable response to chemotherapy, drug resistance develops
in almost all patients with metastases, ultimately leading
to death. The median survival time for patients with metastatic
disease (approximately 14 months) has not improved
to any extent in more than 20 years. 35 In addition, there is a
huge economic burden associated with bladder cancer. Lifetime
health care costs for patients with muscle invasive blad-
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