Arendt et al.

Veterinary Oncology (2025) 2:9 Veterinary Oncology

https://doi.org/10.1186/s44356-025-00021-8

REVIEW Open Access

Genetics of canine cancer: a guide

for the veterinary oncologist
Maja Louise Arendt1,2,3*, Anna Darlene van der Heiden2,3, Raphaela Pensch2,3 and Kerstin Lindblad‑Toh2,3,4

Abstract
Cancer is driven by acquired genetic aberrations that drive the cellular cancer phenotype. In addition, hereditary
genetic risk factors play a central role explaining the large difference in cancer risk between different dog breeds.
There has been a revolution within genetic research over the past decades facilitated by technological advances
and reduced costs. We can use sequencing technologies to characterize genetic changes in cancer cells and iden-
tify markers to diagnose and differentiate cancers. In addition, these technologies can lead to the identification
of druggable targets, leading to advancements within cancer therapy. This review describes some of the advances
within oncogenetics in companion dogs and provides an overview of published genome wide association stud-
ies investigating predisposing genetic risk factors as well as studies investigating somatic cancer-driving mutations
in dogs.

Introduction cancer subtypes based on specific mutations and thera-

For morethan a century it has been known that genetic peutic choice based on cancer mutation profiles [3–5].
aberrations play a role in cancer [1]. However, it is only The World Health Organization classification guidelines
during the past 20 years that research tools have become now include an array of genetic aberrations which are
readily available to characterize the genetic changes used to distinguish different subtypes, guide manage-
inside cancer cells at a base-pair level at high scale. ment and predict prognosis in human patients [6, 7].
The field of cancer genetics has been fostered by rapid Within veterinary oncology there has been a strong drive
advancements in DNA sequencing technology and ana- to sequence cancer types in dogs which serve as good
lytical tools parallelized by a logarithmic reduction in comparative models for human cancer research [8–10].
cost for these technologies [2]. Within human oncology, Similarly, there has been a drive for identifying genetic
genetic test modalities are now widely applied with the risk factors with the view that these findings even can
view that this can improve patient management. Exam- inform human research and increase our understanding
ples of genetic testing, that are applied in the clinical of cancer biology [11–13]. With cancer being the lead-
setting, are testing for germline predisposing variants in ing disease related cause of death in dogs, technologies
families with increased cancer burden, classification of which can improve detection, diagnosis, therapy and
monitoring are warranted [14]. Up until recently, the
*Correspondence:
application of genetic testing in the veterinary oncology
Maja Louise Arendt clinic has been limited. We are now entering an era where
[email protected]
1
the advancement of sequencing methods at reduced cost
Department of Veterinary Clinical Sciences, University of Copenhagen,
Copenhagen, Denmark
allows for application of these test modalities in the clini-
2
Department of Medical Biochemistry and Microbiology, Uppsala cal veterinary setting. This paper provides an overview of
University, Uppsala, Sweden
3
some of the genetic discoveries and tools that are being
SciLifeLab, Uppsala University, Uppsala, Sweden
4
Broad Institute of MIT and Harvard, Cambridge, MA, USA
applied to companion animal oncology. It focusses on
the identification of genetic risk factors predisposing to

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Arendt et al. Veterinary Oncology (2025) 2:9 Page 2 of 11

cancer in dogs and detection of somatic mutations driv- within a specific individual, it does not adequately rep-
ing cancer. Finally, we provide insights into how genetic resent the genetic diversity across multiple individuals
tools can be used to support diagnostics or decision mak- or different dog breeds. In other species, this problem
ing in a clinical setting in the future. has been solved by creating pangenomes. These refer-
ence genomes represent the diversity across a population
The canine genome and provide an improved representation of genetic vari-
A foundation for performing genetic research is a high- ation and haplotypes within a species [25–28]. Although
quality annotated reference genome. Since the first canine a pangenome has not yet become available for dogs, it is
reference genome was released in 2004 (canFam1), there anticipated that it will be in the near future. The applica-
have been multiple efforts to enhance the genome by fill- tion of a canine pangenome to genetic research will likely
ing gaps and improving the annotation resulting in the improve our understanding of genetic diversity within
canFam2 and canFam 3.1 [15, 16]. Annotation is central dogs and our ability to detect structural genetic vari-
to the use of a reference genome, as it determines which ants. When evaluating genetic variation, both in relation
regions of the genome encode genes and other important to germline variation and somatic tumor mutations, it is
functional regulatory elements. The first canine refer- important to distinguish between genetic variants with a
ence genome was based on paired-end shotgun sequenc- functional role, often referred to as driver mutations, ver-
ing of multiple library sizes including bacterial artificial sus genetic variants without a functional role, also known
chromosome libraries (BAC) [15]. Recently, with the as passenger mutations. Distinguishing between driver
development of first short read data such as Illumina and and passenger mutations requires in depth understand-
then long read sequencing technologies such as PacBio ing of the functional implications of the variant and its
and Chromium 10X, it has become possible to generate putative role in disease pathogenesis.
new and improved reference genomes with fewer gaps Genetic studies in dogs are often performed with a
and more contiguous sequences covering complex and comparative intent, as therapeutic targets can be shared
important genome regions, such as the dog leukocyte across species, and knowledge learned from one species
antigen (DLA) loci [17, 18]. can be valuable for the other species, hence promot-
The original reference genome was built on the genetic ing the cancer field overall. In this sense, it is important
sequence from a female boxer, whereas some of the to acknowledge that, although there is a high level of
recent canine reference genomes have been based on homology between the human and the canine genome,
other dog breeds, such as German shepherd (UU_Cfam_ there are also clear interspecies differences, such as genes
GSD_1.0/canFam4), great Dane (UMICH_Zoey_3.1/can- inactivated in one species but not the other, or gene fami-
Fam5) and Labrador retriever (ROS_Cfam_1.0) [15, 17, lies that differ in their sequences and number of active
19, 20]. It has been suggested to use an outgroup such as genes [29]. The PRDM9 gene which has been shown to
the wolf as a reference to reduce the risk of bias related to have a potential role in human cancer is an example of a
variant calling when comparing to a single breed [21]. For gene which has been shown to be inactivated in the dog
research into germline genetic variants and how these genome [30]. The Cytochrome P450 gene families impli-
can predispose to a disease, the reference genome is of cated in drug metabolism are likewise a group of genes
particular importance. Boxers have an increased risk for where species differences are known and where func-
certain neoplastic disorders such as lymphoma, mast cell tional differences potentially can implicate the transla-
tumors and glioma, hence there is a risk that the founder tion of therapeutic trials [31]. However, most of the genes
of this reference genome could be representing risk fac- important for cancer predisposition or that are com-
tors [10, 22, 23]. In this context Tasha, the boxer donating monly mutated within cancer cells are highly conserved
material for the original reference genome, died of cancer. across species with high interspecies homology [29]. The
When aligning sequencing data to a reference genome canine genetic makeup compared to the human counter-
only variants differing from the reference genome are part is summarized in Tables 1 and 2.
usually evaluated. This means that genetic risk variants
could be overlooked if these are represented by the refer- Inherited genetic risk factors
ence genome. Although all the genome builds are of high Differences in cancer frequency between different dog
quality, from an oncological perspective, the UU_Cfam_ breeds have provided evidence that heritable genetic
GSD_1.0/canFam4 was specifically generated with the risk factors likely play an important role in the develop-
view to promote comparative cancer research between ment of cancer in dogs [35]. This becomes particularly
dogs and humans, and 282 Tier1 and 78 Tier2 cancer noticeable when looking at specific cancer types such
census genes were completed in this genome [17, 24]. as urothelial cell carcinoma which is observed more
As each reference genome reflects the genetic diversity frequently in Scottish terriers and histiocytic sarcoma
Arendt et al. Veterinary Oncology (2025) 2:9 Page 3 of 11

Table 1 Comparison of the genome size, chromosomal the approximately 2.5 billion base pairs which make up
arrangements and number of protein coding genes between the dog genome. This results in regions with no cover-
species age and other regions with deeper coverage. As there are
Genome comparison Canine genome Human many positions in the genome which are heterozygotic,
this low coverage means that for most positions only one
Number of chromosomes 39 23
allele is represented. Imputation refers to the statistical
Genome size 2.5 billion bp 3.1 billion bp
prediction of missing genotypes based on known haplo-
Protein coding genes 21,063a 19,868a
types from a reference database built on deep sequencing
a
The number of protein coding genes is based on the Ensembl (version113) of many diverse dogs. In general, to confidently evalu-
annotation summary for the canine genome assembly UU_Cfam_GSD_1.0/
canFam4 and the human genome assembly GRCh38.p14 [32]. Differences in ate the true genotypes across the genome a sequencing
number of protein coding genes between species can in part be explained by depth of ~ 30 × coverage is applied. The advantage of low-
more detailed annotation of the human assignment of larger repertoire of non-
coding genes [33].
pass sequencing is the evaluation of more genetic vari-
ants across the whole genome at a lower cost than deep
sequencing. However, there is a risk that rare variants are
missed if not represented adequately by the imputation
Table 2 Overlap in the genomic sequence between the human
panel and that there is a noteworthy discordance between
(GRCh38) and canine (canFam4) reference genomes from the
241 mammals alignment
the true genotype and the imputed genotype [44].
Most commonly, GWAS analysis has been performed
Genomic sequence overlap Whole genome Coding DNA within a particular dog breed, as it is uncertain whether
sequence(CDS)
genetic risk factors for the same disease are shared
Percentage of the human 84.0% 90.1% between breeds of different origin. Even dogs within
genome (reference) covered the same breed but with different geographical origin
by the canine genome
can show differences in the importance of different risk
Percentage of the canine 81.7% 91.8%
genome (reference) covered loci. Two studies, including dogs from Europe and North
by the human genome America, investigating predisposition to mast cell tumors
Numbers have been generated by Michael Dong, Uppsala University [34] and histiocytic sarcoma in golden retrievers and Bernese
mountain dogs respectively, found that the dominating
risk locus was different between the North American and
which is observed more frequently in flat-coated retriev- European dogs, when analyzed separately [45, 46]. The
ers, with odds ratios of 18.1 and 62.0, respectively, com- majority of canine cancer GWASs have focused on ana-
pared to other dog breeds [36, 37]. The exact mode of lyzing breeds separately (Table 3). However, multibreed
inheritance for cancer within individual dog breeds has GWASs have been performed for some traits. These
not been determined. Complex inheritance caused by require balancing of cases and controls across breeds and
one or multiple low penetrance risk alleles has been pro- taking the multibreed origin into account in the analysis,
posed as well as simpler Mendelian inheritance caused to avoid identifying loci reflecting breed rather than dis-
by risk alleles with high penetrance [38–40]. To identify ease, and to avoid overcorrection of true associations not
genetic risk factors, genome wide association studies present across all included breeds [47]. There are math-
(GWASs) using either broad single nucleotide polymor- ematical models that can be applied to account for popu-
phism (SNP) panels or imputed low-pass whole genome lation structure and the effect of multiple risk alleles in
sequencing (WGS), are being performed. In these stud- multibreed studies [23, 48].
ies, the genotypes of comprehensively phenotyped cases Results from several published GWASs have identi-
and controls for a given disease are compared to identify fied risk loci associated with different types of cancer in
genomic loci that harbor genetic variation associated specific or across several dog breeds (Table 3). Although
with disease risk [41, 42]. GWASs using SNP panels have many studies have identified significant genetic risk loci
the advantage that the genotyping is usually robust. How- related to the risk of developing a specific type of can-
ever, the disadvantage is that there is a risk that there are cer, only a few studies have identified putative functional
no SNPs in the selected panel that tag the genetic varia- variants explaining the disease risk. Interestingly, over-
tion associated with the disease phenotype [43]. Another lapping risk loci on chromosome 5, 11, 14 and 20 have
disadvantage is the identification of often very large been identified in independent studies with different dog
associated regions, making it difficult to identify causal breeds, dog populations and even different cancer types,
risk alleles. Low pass sequencing is a method where emphasizing that predisposing risk loci can be shared
the whole genome is sequenced at a low coverage (usu- across multiple breeds and could predispose to multiple
ally 0.5 to 1 × coverage). This coverage is a mean across different cancer types [12, 13, 45, 50, 52, 54, 55, 58]. With
Arendt et al. Veterinary Oncology (2025) 2:9 Page 4 of 11

Table 3 Summary of selected published genome wide association studies in different canine tumors
Author /Year Breed (s) Cancer Lead SNP from GWAS Genes highlighted as putatively
implicated in disease risk

Arendt 2015 [45] Golden retriever Mast cell tumors US Chr14:11,765,081 Chr14: SPAM1, HYAL4, HYALP1
EU Chr20:45,596,213 Chr20: HYAL1, HYAL2, HYAL3, GNAI2
Combined Chr14: 11,721,433,
11,807,161 (equally associated)
Biasoli 2019 [49] Labrador retriever Mast cell tumors Chr31:34,694,234 Chr31: DSCAM
Evans 2021 [50] Flat-coated retriever Histiocytic sarcoma Chr5:33,001,550 Chr5: PIK3R6
Chr19:(conditional, het- Chr19: TNFAIP6
erozygotes for Chr5 lead
SNP):52,487,724
Hayward 2016 [51] Labrador retriever Mast cell tumors Chr36:16,889,272 Chr36: ITGA6
Hedan 2021 [52] Bernese mountain dog (BMD) Histiocytic sarcoma (HS) BMD HS Chr11:41,161,441 Chr1: RSPH3( other locus than lead
Golden retriever (GR) Mast cell tumor (MCT) BMD HS LSA Chr11:41,161,441 SNP)
Flat coated retriever (FCR) Lymphoma (LSA) BMD GR LSA HS Chr5:32824053a Chr2: PFKFB3 (other locus
Rottweiler (RW) BMD HS MCT Chr11:41,161,441 than lead SNP)
BMD GR HS MCT Chr5: SPNS3, TRPC6, BORCS6,
Chr20:33321282a Chr11: CDKN2A/B, CDKN2B_AS1,
BMD HS Chr11:41215628b MTAP, CAAP1, TUSC1, C9orf72
BMD FCR HS Chr11:41252822b Chr14: POT1, PSMD4, LEP, CPA1,
BMD FCR RW Chr11:41252822b Chr20: FHIT, ARHGEF3, IL17RD,
C3orf67
ChrX: TBL1X, SHROOM
Karlsson 2013 [13] Greyhound (GH) Osteosarcoma GH Chr11:41,375,800 Chr11: CDKN2A/B (Shared locus
Rottweiler (RW) RW Chr1:113,616,670 across breeds)
Irish wolfhound (IW) IW Chr5:12,259,066 Chr1: Multiple genes in this locus
Chr5: BLID
Karyadi 2013 [53] Standard poodle Digital squamous cell carcinoma Chr15:29,371,013 Chr 15: KITLG
Labadie 2020 [54] Golden retriever T-Zone Lymphoma (TZL) TZL Chr8:53,818,371 (TZL) Chr8: DIO2, TSHR
Mast cell tumors (MCT) TZL + MCT Chr14:11794735a Chr14: SPAM1, HYAL4, HYALP1
Letko 2021 [55] Leonberger Osteosarcoma Chr11:39,434,964 Chr11: CDKN2A/B
Melin 2016 [11] English springer spaniel Mammary tumors Chr11:73,290,522 Chr11: CDK5RAP2
Mortlock 2023 [56] Bullmastiff Lymphoma Chr33:8,104,361 Chr33: SENP7, NFKBIZ,
Chr13: MYC (other locus than lead
SNP)
Parker 2024 [48] Shetland Sheepdog (SS) Urothelial cell carcinoma SS alone and SS + multiple Chr13: NIPAL1
Multiple breeds breeds Chr13:44,493,602,
44,508,476, 44,520,164 (SNPs
equally associated)
Shearin 2012 [46] Bernese mountain dog Histiocytic sarcoma EU Chr14:11,076,261 Chr11: CDKN2A/B, MTAP
US Chr11 38,330,565
Combined Chr11:38,330,565
Soh 2023 [57] Border collie Lymphoma Chr18: 18:38,704,682 Chr18: DLA79,
Chr27: WNT10B, LMBR1L, KMT2D,
CCNT1 (other locus than lead SNP)
Tonomura 2015 [12] Golden retriever Hemangiosarcoma (HSA) HSA Chr5:29,892,306 Chr5: TRPC6, STX8
B cell lymphoma (BLSA) BLSA Chr5:33,845,636
HSA + BLSA Chr5:29,892,306
Truve 2016 [23] Multiple breeds Glioma Chr26:9,780,187 Chr26: CAMKK2, P2RX7, DENR
Zapata 2019 [40] Greyhound (GH) Osteosarcoma RW IW Chr1:1,136,161,670 Chr25: FGF9 shared locus
Rottweiler (RW) GH RW IW Chr25:16,672,073 across ­breedsa
Irish wolfhound (IW) Genes nominated in other loci:
CDKN2A/B, AQP4, OTX2, EWSR1
retrogene, BMPER, MTMR7, MARCO,
NELL1, FBRSL1, IGF1, MTMR9,
TANGO2
The table summarizes the author information, breeds involved in the study, cancers / tumor types studied and location of the most associated SNP, as well as putative
genes suggested to be implicated in the disease. Positions are shown on CanFam3.1
a
Indicates that data recycled from other publications have been used in this analysis
b
Analysis performed with a larger imputed SNP dataset
Arendt et al. Veterinary Oncology (2025) 2:9 Page 5 of 11

improved knowledge of the genetic variation across dogs a hotspot mutation is the PIK3CA p.H1047R, which is
and the establishment of large scale canine reference observed in both dogs and humans with mammary neo-
databases such as the Dog10K, it is anticipated that the plasia [8]. The overlapping mutational spectra between
identification of functional risk alleles will be less chal- species reflect shared cancer biology and evolutionarily
lenging in the future [20]. conserved cellular selection pressure, i.e., for a cancer to
develop relatively distinct genetic events need to occur
Acquired mutations in cancer cells that offer a selective advantage for the particular cancer
Cancer is driven by somatic mutations leading to an type. This overlap also facilitates comparative clinical tri-
altered cellular phenotype with dysregulated signaling als in the era of precision medicine. Although there are
pathways in a clonal population of cells. Whilst some clear similarities between species, we also observe spe-
cancers are mainly driven by small genetic alterations in cies differences. As an example, the tumor suppressor
key tumor suppressor and oncogenes, other types of can- gene SETD2 has been shown to be significantly mutated
cer are characterized by larger genomic alterations such a in canine multicentric lymphoma and osteosarcoma,
chromosomal duplications and structural alterations [59– although it is not known as a major cancer driver within
61]. The rapid drop in price for sequencing has made it the human orthologous diseases [9, 73].
possible to characterize the genetic changes that occur in Recently, researchers have started using WGS of tumor
cancer cells in humans as well as dogs and other species / normal pairs, as the price difference between sequenc-
[62–64]. Initially, most studies focused on sequencing ing of exome capture libraries and WGS libraries has
the exonic (protein coding) part of the genome, known decreased. In addition, parallelized computation models
as whole exome sequencing (WES). As the coding part of reduce the analysis time. WGS improves the detection of
the genome accounts for less than 2% of the genome, this genomic rearrangements and structural variants as there
massively reduces the sequencing cost and the amount are no gaps in the sequencing coverage of the genome
of data needing to be analyzed [65, 66]. Different canine [82]. Only approximately 1–2% of somatic mutations
exome panels have been used to capture exons and, in cause changes in the protein coding sequence, whilst the
some instances, also part of the up and downstream reg- remaining mutations are located within the non-coding
ulatory sequences, across the whole genome [8, 10]. As part of the genome [83]. Less attention has been paid to
the knowledge on cancer-driving genes and mutations non-coding mutations in the past. This is partly because
has advanced, smaller exome panels have been intro- of difficulties assigning non-coding mutations with a
duced capturing selected panels of genes that have been functional role. However, one might assume that ~ 10%
shown to be recurrently mutated in cancer cells [67, 68]. of the genome has a regulatory function determining
One such example is the commercially available Canine when and where proteins should be made [84]. Hence,
Search light exome panel, which selectively captures 120 distinguishing functional cancer driving mutations from
genes known to be highly relevant in cancer [69]. This passenger mutations is key [85]. Non-coding mutations
panel can be run as a clinical test on patient material and can play a role in regulating gene expression by affect-
it has been shown that it is possible to run this on both ing enhancer or promoter regions, splice signals and
formalin-fixed paraffin-embedded material, needle aspi- topologically associated domains (TADs) without chang-
rates as well as frozen biopsies, facilitating practical clini- ing the protein coding sequence [85]. Based on that, one
cal application [69]. A comprehensive overview of genes can expect that genes for which the cancer cell relies on
that were identified to be recurrently mutated in canine overexpression, without alteration of the protein cod-
cancers by different sequencing methodologies is pro- ing sequence, will be subject to non-coding regulatory
vided in Table 4. mutations. For example, there are frequent non-coding
There are many similarities between the mutation pro- mutations upstream of the TERT gene in human cancer
files of human and canine cancer cells. This is reflected cells, leading to overexpression of telomerase without
by an overlap in significantly mutated genes within spe- alterations in the coding sequence [86]. Multiple tools
cific cancer types, i.e., genes affected by mutations more have been developed to characterize the non-coding part
than would be expected by chance [81]. As an example, of the genome and assign mutations with a candidate
TP53 is significantly mutated in both humans and dogs role [85]. One approach is using evolutionary constraint
with osteosarcoma, indicating that alterations in this scores. In the Zoonomia project, scores were developed
gene play an important role in driving osteosarcoma by comparing DNA sequences across more than 200
development [9, 72]. In addition, there is also an overlap mammalian species to assign putative functional roles
in hotspot mutations between species characterized by to single base pair positions across the whole genome
specific mutations affecting conserved DNA base pairs [29, 34]. This approach makes it possible to distinguish
leading to the same protein alteration. One example of mutations that are likely to have a functional impact in
Arendt et al. Veterinary Oncology (2025) 2:9 Page 6 of 11

Table 4 Selected publications characterizing somatic mutations in canine tumors

Author Cancer / Tumor type (number of tissues) Method Recurrently mutated genes

Amin 2021 [70] Glioma (83) WES/WGS PDGFRA, PIK3CA, NF1

Arendt 2023 [8] Mammary tumors (55) WES PIK3CA, MUC1, KRAS, TTN, NLRP5, ENSCAFG00000038503,
ARID1A
Das 2023 [71] Soft tissue sarcomas (29) WES TP53, KMT2D
Elvers 2015 [10] B and T- cell lymphoma (105) WES T-cell: PTEN, SATB1, MAP2K1, PSMA1, COX8A,
LTA4H, TBC1D26, PTPN6, NLRP5, GLUD2, KRTAP10-6,
ENSCAF00000031638 B-cell: FAM90A1, DDX3X, TRAF3,
PSMA1, POT1, FBXW7, TP53, PNRC1, TBC1D26, RPL23A,
SETD2, ENSCAFG00000031638
Gardner 2019 [72] Osteosarcoma (37) WES/WGS TP53, SETD2, RPL27A, MLLT10
Gianuzzi 2022 [73] Diffuse large B-cell lymphoma (77) WES TRAF3, SETD2, POT1, TP53, MYC, FBXW7, DDX3X, TBL1XR1,
MAP3K14, ENSCAFG00000046771, PHC3, ABCA13, CIC,
LRP1B, TTN, RARA, PIK3CD, H3C8, EHD3, GBE1, VWF, DIAPH2,
FAM50A, GADD45A, SYNE1, THBS2, PLEC, ETV1, HIVEP3,
MYT1L, LRRN3, MEF2C, ATXN1, KIF21A, TLR5, FSIP2, KDM6A,
TRRAP, SYNE2, SUZ12, LAMA1, ANKRD11, LRRIQ1
Kim 2020 [74] Mammary tumors (143 malignant + 40 benign) WES PIK3CA, KRAS, MKI67, TP53, NKX1-2, SETD1A, PTEN, PIK3R1,
AKT1
Lee 2019 [75] Mammary tumors (20) WES PIK3CAa, PRMT3, cOR8S14, ENSCAFG00000020185,
ENSCAFG00000029433, BHLHA9
Lorch 2019 [76] Pulmonary carcinoma (5) WES (5 dogs) HER2, TP53, PTENa
Additional 73 tumors and 10 cell lines captured
by small selected array)
Megquier 2019 [77] Hemangiosarcoma (47) WES TP53, PIK3CAa, PIK3R1, ORC1, RASA1, ARPC1A
Sakthikumar 2019 [9] Osteosarcoma (66) WES TP53, SETD2, TANGO2, LOXHD1, MYT1L
Saffari 2019 [78] Ameloblastoma (16) WES HRAS
Thomas 2023 [79] Urothelial cell carcinoma (8 BRAF p.V595E + , 28 BRAF WES BRAF, MAP2K1, LRP1B, SMCHD1, ARID1A, CSMD3, KDM5C,
p.V595E -) CSMD1, RYR2, KMT2D, STAG2, MSH6, PBRM1, ATM, MDC1,
Wang 2017 [68] Hemangiosarcoma (20) WES TP53, PIK3CA
Wong 2019 [62] Oral malignant melanoma (65) WES NRAS, TP53, RP1, FAT4, PTPRJ, CSMD3
Wong 2023 [80] Urothelial cell carcinoma (87) WES BRAF, TTN, ZFHX4, CSMD3, FSIP2, CDH12, USH2A, LRP1B,
HMCN1, ARID1A, PCDH17, HMCN2, TNNI3K, MGAM2, LRP2,
ENSCAFG00000007873, KDM6A, LAMA2, FLNA, MDN1,
GRIK2, COL11A1, VCAN, XIRP2, ZNF536, ZNF804B, TENM3,
DNAH7, PCDH9
The table summarizes the author, cancer or tumor types implicated in the study, target of sequencing (whole exome sequencing (WES), whole genome sequencing
(WGS)) and genes found to be mutated in >5% of tumors and in at least three individuals. Differences in data curation and filtering as well as methods for
determination of significantly mutated genes are variable across studies
a
Data based on sequence capture of selected genes

cancer. Using this approach, it has been possible to iden- to environmental carcinogens such as UV light, tobacco
tify genes enriched for non-coding constraint mutations smoke or ionizing radiation [89]. In dogs, which have a
in tumor / normal sequencing data from human medul- shorter lifespan and shorter time of exposure to carcin-
loblastoma and glioblastoma [87, 88]. This methodology ogens, it has been shown that the aging signature is the
is currently being applied to ongoing canine and human most dominant signature across different cancer types [9,
cancer sequencing studies. 63]. There is, however, evidence that some tumors carry
Aside from understanding which genetic changes a signature that, in humans, has been related to UV light
drive cancer, sequencing of cancer tissue can also be exposure [63]. In addition, a mutational signature that
used to understand what causes the mutational process has not been characterized in humans and which appears
by evaluating the mutational signature. Combinations to be frequent in cancers from golden retrievers, has also
of mutation types reflect underlying extrinsic or intrin- been identified [9, 63]. One could speculate that this sig-
sic causes. Those can be infidelity of DNA replication nature is caused by germline genetic variants segregating
and the accumulation of mutations during aging as well within this breed that are predisposing to the mutational
as heritable genetic defects in DNA repair or exposure process, though this link has not been confirmed.
Arendt et al. Veterinary Oncology (2025) 2:9 Page 7 of 11

Clinical applications of DNA technology in veterinary shepherds is an example of a genetic variant that can
oncology identify which dogs carry risk factors for this neoplas-
Although we are still in the early phase of characterizing tic disorder [90]. A genetic test for cancer associated
genetic variants that predispose to cancer, as well as iden- risk alleles is available to guide the selection of Bernese
tifying somatic cancer-driving mutations in companion mountain dogs before breeding [91, 92]. Though this
animals in depth, sequencing and genotyping technolo- test has been available for several years, we are still
gies offer enormous prospects for clinical use (Fig. 1). awaiting data showing the long term effects of this test.
Before applying a genetic test to a clinical setting retro-
Germline screening of risk variants spective validation in independent patient cohorts and
Identifying germline variation predisposing to cancer is functional validation of genetic cancer predisposing vari-
an important tool to understand underlying causes of ants should be performed. As for now, breed appears to
cancer. This can be used for selective breeding away from be the most reliable risk predictor [35]. However, with
risk carriers, to identify individuals at risk of developing larger initiatives and validation studies, improved tests
early onset disease who could benefit from entering a for risk prediction could become available, which pref-
screening program and to identify potential markers for erable can be used within and across breeds. In addition
preventing disease or reducing risk. However, with few to determining individuals at risk of disease, germline
exceptions, we are not yet in a position where we pro- genetic profiling can also be used to predict individuals
spectively and reliably can predict cancer risk in dogs at risk of developing severe adverse effects or having an
based on genetics [90]. The canFam 3.1 chr5:42,186,445 altered response to antineoplastic drugs. A well charac-
A > G autosomal dominant genetic variant causing renal terized four base pair deletion in the ABCB1 gene has
cystadenoma and nodular dermatofibrosis in German been shown to increase the risk of severe chemotherapy

Fig. 1 Some of the applications of genetic testing in the veterinary oncology clinic. Genetic testing holds great promise in the oncology clinic
as a tool for identifying individuals at greater risk of developing cancer as well as characterizing cancers once they have developed. Circulating
cell-free DNA (ccfDNA)
Arendt et al. Veterinary Oncology (2025) 2:9 Page 8 of 11

induced neutropenia in dogs receiving drugs which In comparison the median TTP was only 141 days for
are transported by the ABCB1 encoded p-glycoprotein dogs without KIT mutated tumors treated with masitinib
transporter [93, 94]. In humans a larger panel of genetic [101].

SearchLight DNA™ sequence capture panel, showed that

variants have been characterized which can influence the A study investigating the prognostic value of the
response or risk of adverse effect from chemotherapy and
other therapeutic modalities which suggest that more certain genetic aberrations were associated with a worse
could be discovered in dogs [95, 96]. outcome suggesting that the panel could offer prognos-
tic information. In addition, the study also showed an
Somatic mutations for screening, diagnosis and targeted improved outcome in dogs receiving treatments chosen
therapy on the basis of their tumor’s mutation profile. Though
The detection of somatic mutations in cancers has a solid this sounds promising, it should be taken into account
clinical application and can be applied as a tool to screen, that the study included 127 dog representing 26 cancer
diagnose, classify and monitor neoplastic disease. types and hence in such a heterogenous dataset there
Early detection of circulating cell-free DNA (ccfDNA) could be other parameters influencing outcome [67]. In
from cancer cells, that is short DNA fragments around humans, precision medicine, as in targeted treatment for
160 nucleotides in length originating from cells undergo- specific mutation profiles in cancer cells, is being widely
ing apoptosis, offers the opportunity for cancer screening applied with a large panel of drugs approved for specific
and early detection as well as providing a minimally inva- mutations [102]. Another clear role for applying genetic
sive tool to aid in confirming a diagnosis of cancer [97]. methods in the oncology clinic is the easing of staging
Being able to characterize small amounts of cancer procedures and minimally invasive screening for disease
cell DNA from fine needle aspirates or fluid samples relapse. We already see several commercial applications
containing cancer cells provides the possibility to distin- of genotyping and sequencing technologies on the veteri-
guish reactive processes from neoplastic processes and nary market for both cancer screening as well as cancer
perhaps even assigning a provisional diagnosis, reduc- characteristics and drug target identification [67, 103,
ing the need for larger, more invasive biopsies [98]. The 104]. These tests hold great promise for improving the
urine sediment-based BRAF mutation screening test workflow in the oncology clinic and allowing companion
for urothelial and prostatic carcinoma in dogs is already animals to enter the era of precision medicine. We need
widely applied with a reported sensitivity of up to 85% to consider that the research data available for compan-
and a specificity reaching 100% [99]. It aids in confirming ion animals is still limited. Long-term validation studies
a diagnosis without the need for larger tissue biopsies, are needed to validate the precision of these tests. It is
which increase the risk for complications and potentially also important to determine whether early cancer detec-
cancer seeding [99, 100]. This test is facilitated by the tion will lead to an overall survival benefit in veterinary
strong dependency of urothelial carcinoma on the activa- cancer patients. Furthermore, caution should be taken in
tion of the BRAF oncogene and the conserved activation the interpretation of single point mutations. For instance,
hotspot of this gene, allowing for detection by PCR based we know that there is an overlap between some of the sig-
methods [99]. Further the test is enabled by the abun- nificantly mutated genes and hotspot mutations between
dant exfoliation of cancer cells directly into the urine. benign and malignant disease. One such example is the
By combining large-scale sequencing data from canine PIK3CA hotspot mutations which are frequent in both
cancer with clinical records and patient outcomes, we benign and malignant canine mammary tumors as well
might be able to identify prognostic predictors for patient as hemangiosarcoma [8, 68]. More than a million human
outcome. In addition, major cancer-driving genes could cancer samples have been characterized by mutational
also provide novel therapeutic drug targets and provide profiling leading to genetic testing now being widely
tests to select which patients are likely to respond to a applied in human oncology [24]. In comparison the num-
given therapy. One such example already existing in vet- ber of cancer samples in dogs which have been charac-
erinary oncology is the veterinary licensed drug masitinib terized are sparse and the integration of detailed clinical
(Masivet, AB Science, France). It was licensed in Europe and pathological data into sequencing studies have been
for use in dogs with non-resectable mast cell tumors that limited (Table 4). Hence, the full clinical utility of genetic
carry activating mutations in the KIT oncogene, based on testing in veterinary oncology is still to be discovered.
evidence from an initial clinical trial that showed signifi-
cantly prolonged time to progression (TTP) in dogs with Conclusion
KIT mutated tumors [101]. In the study the median TTP The field of canine cancer genetics has been mov-
for dogs with KIT mutated tumors was 241 days com- ing rapidly in recent years. We are in a position where
pared to 83 days for the placebo treated control group. we have tools and resources available to improve the
Arendt et al. Veterinary Oncology (2025) 2:9 Page 9 of 11

characterization of cancer in dogs. There are several 9 Sakthikumar S, et al. SETD2 is recurrently mutated in whole-exome
sequenced canine osteosarcoma. Cancer Res. 2018;78:3421–31. https://​
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This is a rapidly developing field with a large commer- reveals somatic mutation patterns reflecting genetic background.
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for how best to use these technologies to support clinical factors associated with canine mammary tumours. PLoS Genet.
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12 Tonomura N, et al. Genome-wide association study identifies shared
oncologists, pathologists and geneticists will guide the risk loci common to two malignancies in golden retrievers. PLoS Genet.
way for how we can use these technologies to benefit our 2015;11: e1004922. https://​doi.​org/​10.​1371/​journ​al.​pgen.​10049​22.
patient population the most. 13 Karlsson EK, et al. Genome-wide analyses implicate 33 loci in
heritable dog osteosarcoma, including regulatory variants near
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Competing interests consortium advances the understanding of demography, genome
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