Page 23 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

2 PART I The Biology and Pathogenesis of Cancer

maintain normal organ structure and function. Recent studies Lung
by Tomasetti and Vogelstein identified a strong correlation (r = 10 –1 (smokers)
0.81) between the total number of stem cell divisions and the life-
VetBooks.ir time risk of cancer arising from 31 distinct tissues (Fig. 1.1A). germ cell Testicular Colorectal
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Ovarian
In contrast, no significant correlations were seen between the risk
for these cancers and heritable or environmental and geographic Lifetime Risk –3
factors. 10 10
The take-home message from this work is that DNA replica- Small intestine
tion (R) represents a major risk factor for cancer, joining heritable Head Duodenum
risk (H) and environmental risk (E) as the major causes of muta- 10 –5 osteosarcoma
tions that can lead to cancer (see Fig. 1.1B). Heritable risk arises
from mutations in the germline, such as those in the genes BRCA1 10 5 10 7 10 9 10 11 10 13
and BRCA2, TP53, and CDKN2A that are associated, respectively, A Total Stem Cell Divisions
with breast cancer risk, with Li-Fraumeni syndrome and suscepti-
bility to many cancers, and with susceptibility to melanoma and
pancreatic carcinoma. Only one heritable cancer syndrome has Hereditary Replicative Environmental
been identified in domestic dogs. A germline mutation of the
BHD gene encoding folliculin was identified in a family of Ger- B
man shepherd dogs that showed susceptibility to a syndrome of
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renal cystadenoma and nodular dermatobibrosis ; however, con- HN Th
trolled breeding practices make it difficult for heritable cancers NHL
associated with single gene mutations to be perpetuated in domes- Lu E M
tic animals outside a laboratory environment. Lk
In animals, and specifically in dogs, in which the lifetime risk Br Li
of cancer seems to be approximately equivalent to that of humans, K S
the apparent increased prevalence of certain tumor types in certain P CR
breeds (closed gene pools) suggests that incompletely penetrant, U O
heritable factors might contribute to cancer causation. Indeed, Bl
even relatively minor traits that do not considerably alter the phe- C
notypic appearance have been found to be associated with risk.
Perhaps this is most easily appreciated in greyhounds; registered 0% 100% Percentage of driver mutations attributable to each factor
racing greyhounds are at higher risk of developing osteosarcoma B
(OSA) than American Kennel Club (AKC) “show” greyhounds.
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This suggests that different components of risk could have become • Fig. 1.1 (A) The relationship between the number of stem cell divisions in
established in the founders of the racing and show greyhound lin- the lifetime of a given tissue and the lifetime risk of cancer in that tissue.
eages. In the racing greyhounds, however, part of the risk could (B) Etiology of driver gene mutations in women with cancer. For each of
18 representative cancer types, the schematic depicts the proportion of
be due to concussive forces during training and performance rac- mutations that are inherited due to environmental factors or due to errors
ing, which have the potential to create microfractures and activate in DNA replication (i.e., not attributable either to heredity or to environ-
chronic repair processes. ment). The sum of these three proportions is 100%. The color codes for
Environmental risk factors include chronic exposures to hereditary, replicative, and environmental factors are identical and span
genotoxic agents, including habitual use of tobacco products; white (0%) to brightest red (100%). B, brain; Bl, bladder; Br, breast; C,
high-energy radiation from the sun or from occupational haz- cervical; CR, colorectal; E, esophagus; HN, head and neck; K, kidney;
ards, such as uranium mining; workplace chemicals, such as Li, liver; Lk, leukemia; Lu, lung; M, melanoma; NHL, non–Hodgkin lym-
vinyl chloride; and agents that promote chronic inflammation phoma; O, ovarian; P, pancreas; S, stomach; Th, thyroid; U, uterus.
and activate tissue repair processes unremittingly, such as asbes- (Reproduced with permission. (A) From Couzin-Frankel J. Biomedicine:
tos. Tobacco use and sun exposure account for a large portion of the bad luck of cancer. Science. 2015 Jan 2;347(6217):12. doi: 10.1126/
science.347.6217.12.; Tomasetti C, Vogelstein B. Variation in cancer risk
human cancers worldwide. The risk of cancer from these expo- among tissues can be explained by the number of stem cell divisions.
sures has been compounded in the past century by the increased Science. 2015 Jan 2;347(6217):78-81. https://doi.org/10.1126/sci-
longevity of human populations, which allows more time for ence.1260825. Fig. 1.1. (B) Illustration by Corinne Sandone © 2017 Johns
mutations to accumulate. In animals, strong associations have Hopkins University. Used with permission.)
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been established between exposure to ultraviolet radiation from
the sun and some skin cancers in dogs, cats, cows, and horses; their effects might be compounded by the increased life span
however, these account for a small proportion of cancer in these provided by modern veterinary care.
populations. Likewise, exposure to environmental tobacco Replicative risk of cancer is ever present, and it increases inexo-
smoke seems to increase the risk for a small proportion of can- rably with age. The stochastic nature of replicative risk is reflected
cers of dogs (nasal carcinoma) and cats (possibly lymphoma). in the molecular heterogeneity observed in histologically similar
The association between risk for cancer and exposure to other tumors, and the strong correlation between cancer and advanced
chemicals in dogs, cats, and other domestic animals is a topic of age in dogs suggests that the replication-associated R factor likely
controversy; such exposure is likely to account for a small frac- is responsible for an even greater proportion of cancers in this spe-
tion of cancers seen in these species, although, as in humans, cies than it is in humans.