Page 33 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

12 PART I The Biology and Pathogenesis of Cancer

human tumors. The prototypical example was a structural aber- from the GWAS suggested a role for CDKN2 and the associated
ration resulting from a balanced chromosomal translocation that cycle regulatory processes in OSA risk; the significance of these
pathways was independently confirmed as a key indicator of the
creates a fusion gene composed of most of the BCR gene (located
VetBooks.ir on chromosome 22 in humans and on chromosome 26 in dogs) prognosis in canine OSA using gene expression studies. 41,137,138 In
the case of HSA and B-cell lymphomas, two histologically differ-
and a truncated form of the ABL gene (coincidentally located on
chromosome 9 in both humans and dogs) in CML. 123 Both trans- ent tumors that occur commonly in golden retrievers, the GWAS
locations give rise to a derivative chromosome, the Philadelphia identified two shared risk loci on chromosome 5. 133 This observa-
(Ph) chromosome in humans and the “Raleigh” chromosome in tion suggests that HSAs and B-cell lymphomas might originate
dogs. Certain numeric aberrations (changes in DNA copy num- from a common lineage of hematopoietic progenitor cells. 119,139
ber) are similarly conserved in both species in a variety of can- Such meticulous work has improved our understanding of how
cers, including lymphoma, soft tissue sarcomas, OSA, and brain distinct heritable traits segregate with cancer phenotypes in dogs,
tumors. 124–129 although it remains to be seen if these traits will be shared between
The development of specific tumors from cells harboring closely related breeds or whether they contribute to risk indepen-
such shared mutations is not surprising, but why would homol- dently among different breeds. 127
ogous, highly conserved pathologic rearrangements, deletions, Next-generation sequencing of tumor and normal exomes
or amplifications occur in cells from distinct organisms? One has been completed for canine lymphoma (Fig. 1.8), HSA, and
possibility is selection for phenotype; in other words, the genetic OSA. 41,59,140–142 In the case of B-cell lymphomas, 64 exomes were
change “freezes” development at a particular stage for that cell sequenced from golden retrievers and cocker spaniels. The tumors
lineage and enhances growth and survival compared with nor- had an average of 500 somatic mutations each, of which about 20
mal cells in the niche. But it is also possible that these mutations were nonsilent coding mutations. The most common recurrently
are evolutionarily related on a mechanistic basis. For example, mutated genes were TRAF3, FBXW7, and POT1, which regulate
rearrangements of the immunoglobulin heavy chain locus and signaling pathways of telomerase and autoimmunity. FBXW7
the MYC locus are thought to be due to recognition of MYC mutations, in particular, were found in 15 of 54 (28%) golden
flanking sequences by the recombinase enzyme system. 123 No retriever samples and in 1 in 10 (10%) cocker spaniel samples. The
such mechanism is known to be operative for other defined sites, two most common, nonsilent mutations in FBXW7 were mutu-
so these other mutational events could occur stochastically, with ally exclusive and created arginine to leucine amino acid substitu-
their recurrent characterization across multiple species being the tion at positions 470 and 484, respectively. These residues are also
result of the selective advantage provided by the acquired gene to hotspots of FBXW7 mutation in human cancers.
a cell of a highly specific lineage under highly specific conditions. The exomes in T-cell lymphomas were more heterogeneous;
Another possibility is that they are related to the nuclear anat- still, 7 of 16 peripheral T-cell lymphomas from boxers harbored
omy of the cell and specifically caused by proximity of chromo- mutations in the PTEN-mTOR pathways. The data, however,
somal regions, cellular stress, inappropriate DNA repair (or, as is not sufficient to distinguish whether this is due to a genetic
mentioned previously, recombination), and DNA sequence and propensity for mutations of PTEN and other functionally related
chromatin features, such as reuse breakpoints. 130 A third intrigu- genes in boxers, or to an association in which such mutations
ing possibility is that cellular genomes are reverting to a confor- favor selection for ontogenetically related tumors. Because genes
mation that was found in a common ancestor (thus the high in the PTEN-mTOR axis are also common targets of mutation in
affinity and specificity between the rearranged chromosomal seg- human cancers, studies of canine T-cell lymphoma might help to
ments lead to the same recurrent event in many patients) but lost unravel their contribution to the origin and progression of cancer
during the process of chromosomal reorganization in evolution, in a vulnerable breed and provide a discovery platform to test the
or that these sites represent targets for gene deletions or duplica- safety and efficacy of drugs that target these pathways.
tions that have been repeatedly advantageous to species under In the case of HSA, independent reports by two groups doc-
conditions of natural selection and so have become embedded in umented recurrent somatic mutations of TP53 and PIK3CA in
their contemporary descendants. more than 50% of tumors within a background of many “private”
In dogs and other domestic animals, the coexistence of genetic mutations (i.e., unique to individual tumors). And in the case of
isolates in closed populations we call “breeds,” along with animals OSA, two independent reports identified somatic mutations of
of mixed breeding, lends itself to the study of how a relatively TP53 as the most common genetic abnormality in this tumor.
homogeneous background influences cancer in outbred popula- Exome sequencing also confirmed that chaotic OSA and HSA
tions. Dogs were the first species in which genetic background genomes had extensive, albeit minimally overlapping, copy num-
was shown to mold tumor genomes and tumor gene expression ber aberrations, which were far in excess of those found in lym-
profiles, highlighting the utility of comparative approaches to phomas 124,125,128 ; predictably, translocations resulting in de novo
understanding cancer genetics. 55,128,131 Over the past decade, fusion genes also were more frequent in HSA and OSA than they
technologic advances in next-generation sequencing and bioinfor- were in lymphoma. 42
matics have improved our understanding of these relationships; Most of the coding mutations identified by exome sequencing
GWASs have identified disease-specific risk alleles in histiocytic were confirmed in RNAseq data sets from the same cases, allow-
sarcoma, 132 squamous cell carcinoma of the digit, OSA, canine ing us to extend the observations to additional dogs and other
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mammary tumors, B-cell lymphomas and HSA, 133,134 mast cell breeds and then to conclude that common somatic mutations in
tumors, 135 and brain tumors 136 in susceptible dog breeds. In the lymphoma, HSA, and OSA are not associated with breed, age, sex,
case of OSA, the GWAS revealed 33 unique risk loci in three or hormonal status (intact or neutered).
breeds, and although none obviously overlapped, the existence of Genomic studies, including GWAS, comparative genomic
shared risk alleles might have been masked because they reside hybridization, and next-generation sequencing, are expected to
within fixed regions in some breeds (Fig. 1.7). Convergent data proceed in cats with the advent of the feline genome sequence. 143,144
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