DOI: https://doi.org/10.52973/rcfcv-e32163
Received: 02/06/2022 Accepted: 04/07/2022 Published: 23/08/2022
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Revista Cientíca, FCV-LUZ / Vol. XXXII, rcfcv-e32163, 1 - 6
ABSTRACT
In non-ovariectomized female dogs, breast tumors are the most
frequent neoplasms. There are several points where canine and
human breast tumors have clinical and molecular similarities. BRCA1
and BRCA2 genes have been extensively studied in both species.
Regarding dogs, alterations in BRCA1 and BRCA2 have been identied
in the development of breast tumors in different breeds. In this work,
it was proposed to study exons 22 and 23 of the BRCA1 gene and
exons 11 and 27 of the BRCA2 gene, in female dogs. It was studied two
groups of female dogs, with or without mammary tumors. Regarding
the genetic study of 15 loci, six were polymorphic, all of them were
singles nucleotides polymorphisms (SNPs), while the other nine were
monomorphic. It was obtained a low allelic variability, but at the
population level, the tumor group has greater variability than the
control group. On the other hand, the different analyses of possible
groupings were negative, and it was not possible to clearly dene
groups with the parameters it was used. The foregoing may be a
consequence of numerous factors such as characteristics inherent
to the populations studied, such as the size of both populations; the
breeds studied; tumor diversity. As it was mentioned before, the genes
studied in this work have been widely related to breast cancer, both in
humans and in dogs. In the former, they have been highly implicated
in hereditary tumors. In dogs, it do not have that information. In the
present case, it was founded no relationship between each of the
markers studied and the occurrence of mammary tumor between
the problem group and the control group.
Key words: Canine BRCA1 gene; canine BRCA2 gene; mammary
tumours in dogs
RESUMEN
En perras no castradas, los tumores de mama son las neoplasias más
frecuentes. Hay diversos puntos en que los tumores en humanos y
caninos presentan similitudes, tanto clínicas como moleculares. Los
genes BRCA1 y BRCA2 han sido ampliamente estudiados en ambas
especies. En lo que respecta a perros, las alteraciones en BRCA1 y
BRCA2 se han identicado en el desarrollo de tumores mamarios en
diferentes razas. En este trabajo, se procedió a estudiar los exones
22 y 23 del gen BRCA1 y los exones 11 y 27 del gen BRCA2 en perros. Se
estudiaron dos grupos de perras, con y sin tumores mamarios. De los
15 loci analizados, seis fueron polimórcos, todos polimorsmos de
nucleótidos únicos (SNPs), mientras que, los nueve restantes fueron
monomórcos. Se obtuvo una baja variabilidad alélica, aunque a
nivel poblacional, el grupo con tumores tuvo mayor variabilidad que
el grupo control. Por otra parte, los diferentes análisis de posibles
agrupamientos fueron negativos, no fue posible diferenciar ambos
grupos con los parámetros empleados. Estos resultados pueden ser
debidos a numerosos factores como: características inherentes a las
poblaciones estudiadas como ser su tamaño; las razas estudiadas;
la diversidad tumoral. Como ya se mencionó, los genes analizados
en este trabajo han sido ampliamente relacionados a los tumores
mamarios, tanto en humanos como en caninos. En los primeros tienen
una gran implicación en los tumores de base hereditaria, dato con
el que no se contó en el presente caso. Aquí no se encontró relación
entre ambos marcadores estudiados y la ocurrencia de tumores
mamarios entre el grupo problema y el grupo control.
Palabras clave: Gen BRCA1 canino; gen BRCA2 canino; tumores
mamarios en perras
Analysis of polymorphisms in BRCA1 and BRCA2 genes in a population
sample of canines from Uruguay
Análisis de polimorsmos en los genes BRCA1 y BRCA2 en una muestra poblacional de caninos de
Uruguay
Alicia Decuadro
1
, Silvia Llambí
2
, Alejandro Benech
1
and Rosa Gagliardi
2
*
1
University of the Republic, Faculty of Veterinary Medicine Hospital. Montevideo, Uruguay.
2
University of the Republic, Faculty of Veterinary Medicine, Genetics and Animal Improvement Unit. Montevideo, Uruguay.
*Email: rgagliar@gmail.com
BRCA1 and BRCA2 genes in dogs / Decuadro et al. _________________________________________________________________________________
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INTRODUCTION
In dogs (Canis lupus familiaris), particularly in non-ovariectomized
(spayed) females, breast tumors are the most frequent neoplasms,
accounting for about half of cancer cases worldwide described [7, 15,
21]. On the contrary, less than 1% of mammary gland neoplasms occur
in male dogs [15, 23]. Tumor incidence correlates with life expectancy,
and is signicantly reduced by ovariohysterectomy, before the third
estrus, in young female dogs. The incidence is increased by the use
of estrous-inhibiting-progestagens [9, 12].
Approximately half of canine mammary tumors are malignant, and
half of them have metastasized by the time of the initial diagnosis.
Two-thirds of these tumors occur in the caudal abdominal, and inguinal
breasts. More than 50% of cases involve multiple glands. They may be
attached to the skin, but they usually do not adhere to the underlying
body wall, this being a more frequent feature in malignant tumors;
in addition, they may also be covered by ulcerated skin [12, 23]. Dog
mammary neoplasms usually appear as circumscribed nodules with
variable size, consistency, and mobility and they can also be associated
with ulceration and local inammatory reactions. Multiple tumors are
often seen in a single mammary gland, or they may simultaneously
involve multiple glands, and may be of different histological types
[8, 9]. The tumor with the worst prognosis is the one that will always
determine the clinical course of the patient [3, 4]. The inguinal and
caudal abdominal mammary glands are more frequently affected than
the thoracic glands, which is due to the greater volume of breast tissue
in these glands [5].
In this species, broadenomas are among the most benign breast
tumors, while solid carcinomas are among the most common
malignant tumors, followed by tubular adenocarcinomas [18]. The
average age of affected female dogs is 10 to 11 years old (YO) (range 2
to 16 YO). In younger animals, benign tumors are usually more frequent
than malignant ones [15, 17].
On the other hand, the development of mammary tumors in female
dogs is known to be hormone-dependent. Compared with intact
female dogs, the risk for malignant tumors in female dogs spayed
before the rst estrus is 0.5%, if spaying is after the rst estrus it
increases to 8%, and it increases to 26% if spaying is after the second
estrus [2, 10, 16, 20]. Spaying after the latter estrus does not reduce
the risk for malignant tumors, although it does appear to decrease
the risk for benign tumors [9, 17, 18].
There are several points where canine and human breast tumors
have both clinical and molecular similarities [1, 22, 24]. In addition to
spontaneous tumor presentation, clinical similarities between human
breast tumors (HBC) and canine mammary tumors (CMT) include age
of onset, hormonal etiology, and disease evolution. In addition, factors
affecting the outcome of the disease, including tumor size, stage,
and lymph node invasion, are similar in both species. In particular,
in situ ductal carcinomas in both HBC and CMT mammary glands
are particularly similar in their pathological, molecular, and visual
characteristics.
One of these elements that has led to different studies is the
hereditary risk of breast cancer, as well as the alterations that
may take place at the genetic level. In these aspects, both BRCA1
and BRCA2 genes, as well as tumor suppressor genes, have been
extensively studied [10, 16, 17, 22, 24]. These studies have been mostly
performed in humans, a species where mutations in these genes
leads to the accumulation of Deoxyribonucleic acid (DNA) damage
and an increased possibility of developing breast and ovarian cancer
[17, 22, 24]. Most mutations in these genes were shown to cause
protein truncation through indels, nonsense mutations, cut-and-
splice variants, or rearrangements [17].
Regarding dogs, alterations in BRCA1 and BRCA2 have been identied
in the development of breast tumors in different breeds [17]. In
particular, the BRCA1 gene is involved in tumor etiopathogenesis,
loss of BRCA1 protein function results in defective DNA due to the lack
of DNA repair, leading to a decreased expression, which is a critical
step in the development of breast cancer [13, 23]. With regard to the
BRCA2 gene, its mutations are associated with the development of CMT
[14, 22, 24]. It should also be mentioned that given the characteristics
of CMTs and their similarities with HBCs, dogs could be an excellent
model for the study of the disease in humans [1, 11].
In this work, it was proposed to study exons 22 and 23 of the BRCA1
gene and exons 11 and 27 of the BRCA2 gene in dogs.
MATERIALS AND METHODS
This work was carried out in the Department of Clinics and Veterinary
Hospital, and in the Department of Genetics and Animal Improvement
of the Faculty of Veterinary Medicine of the University of the Republic
(UdelaR), Uruguay. This study was approved by the Ethics and Animal
Use Committee (number 518).
Case selection criteria
CMT cases were selected according to the clinical characteristics
previously described in the species. It was worked with animals with
nodules/tumors in their mammary region with clinical characteristics
consistent with tumors. It was selected females between six and
12 YO, all were clinically examined and classified as suitable for
subsequent work with them. For the control cases, it was selected
females within the same age range, without oncological pathologies,
that have been admitted to the Hospital of the Faculty of Veterinary
Medicine for other reasons. All patients were admitted through the
general medicine section, where the rst clinical examination was
performed and the corresponding routine management was indicated.
Female dogs without tumors, which would be part of the control group,
underwent abdominal ultrasound (ultrasound equipment: TOSHIBA
Nemio MX, Japan) and chest X-ray (x-ray equipment: Carestream,
España), in order to rule out any oncologic pathology.
Animal study groups
Group 1: female dogs with mammary tumors: 32 females of the above
mentioned ages, of breeds: Poodle, Labrador Retriever, Cimarron,
Cocker Spaniel, German Shepherd, Boxer, Pitbull, Rottweiler, Bernese
Mountain Dog, Golden Retriever, Dogo, American Staffordshire Terrier,
Chihuahua, and mixed breeds. All the female dogs had blood values
within the reference parameters. It was selected intact (not spayed)
female dogs. Eleven of them had given birth. It was performed a
clinical examination that included complete case history: age, breed,
reproductive status, and tumor characteristics, mainly: location, size,
evolution, whether single or multiple. It was registered the location of
the tumors in the mammary chain, number, size, consistency, color,
adhesions, presence of pain and ulceration.
In each patient, a thorough physical examination was carried
out, including individual inspection and palpation of each breast of
both chains, and of the regional lymph nodes (axillary and inguinal).
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None of the female dogs had lymph node metastases or abdominal
metastases. This was ruled out by palpation of satellite lymph nodes
and abdominal ultrasound. Two female dogs had lung metastases.
The guardians of the selected patients received information
explaining the objectives of the study, the associated risks and
benets, the design of the activities to be carried out, and required
interventions, as well as any possible conict of interest of the
personnel involved in the study, and had to provide their signed
consent before each surgery (treatment used).
Group 2: Control cases: 13 adult canine females from six to 12 YO,
intact (not spayed) who were admitted into the Hospital of the Faculty of
Veterinary Medicine (UdelaR), with other non-oncologic pathologies. As
in the previous group, there were different breeds: cross breeds, Border
Collie, Blood Hound, Poodle, Great Dane. All animals were examined
by a Veterinary Doctor by means of a general and particular objective
examination in order to determine their health status.
Blood sampling and DNA extraction
Blood was collected from all the female dogs under study under
aseptic conditions and considering animal welfare standards. Collection
was carried out using tubes with Ethylenediaminetetraacetic acid
(EDTA) as anticoagulant, and samples were kept at -18°C in freezer
Panavox (China) until further processing. DNA extraction was carried
out in the Genetics Laboratory of the UdelaR, with the Qiagen kit
(DNeasy Blood & Tissue Kits in spin column). All DNA samples were
then quantied using NanoDrop ND 1000 spectrophotometer (Thermo
Fisher Scientic, USA) with total spectrum (220-750 nanometers (nm)).
The DNA samples were sent to GeneSeek, ink. in the USA, to study
the genotypes of mutations in the BRCA1 and BRCA2 genes in both
tumor and control female dogs. 25 nanograms per microliter (ng·μl
-1
)
per sample were sent in solution.
It was analyzed exon 22 and 23 of the BRCA1 gene, and exon 11 and 27
of the BRCA2 gene (ENSCAFG00000014600 and ENSCAFG00000006383
respectively).
Statistical analysis
For calculations of population variability and genetic structure
statistics: allele frequencies of polymorphisms, Hardy-Weinberg
equilibrium, Wright’s F statisticians (F
IS
, F
IT
, F
ST
), and Correspondence
Factorial Analysis (CFA), it was used the GENETIX V 4.05 freeware [3].
Cluster analysis of the identied polymorphisms by singles nucleotides
polymorphisms (SNPs, indels) was performed according to the
clinical characteristics of the two populations (animals with tumors/
animals without tumors), tumor stage, and breeds; for this it was used
bioinformatic tools such as cluster analysis or hierarchical clustering
(Hclust function of the Stats package in R programming code, freely
distributed).
RESULTS AND DISCUSSION
Allele frequencies
The studied samples were sent to GeneSeek, Lincoln-Nebraska,
USA, to be genotyped for 15 different markers (SNPs or indels). This
was done in both groups, in the group of female dogs with tumors
and in the control group (female dogs without tumors). The data were
analyzed using the freely available Genetix software. From these
analyses, it appears that of the 15 loci studied, six were polymorphic (all
of them SNPs), and the other nine were monomorphic (no variation).
Polymorphic loci were: EXON 11 A>C (23125: rs851104585), EXON 11
A>G (22986: rs851293339), EXON 11 A>C3 (23382: rs23244160), EXON
11 A>G1 (23203: rs851048998), EXON 11 A>G3 (23469: rs851757509) and
EXON 23 C>T (64182: rs850652146). It can be seen that polymorphic
loci are the same in both populations (TABLE I). It was found ve of
these SNPs in exon 11 of the BRCA2 gene and one SNP in exon 23 of
the BRCA1 gene in both tumor and control female dog groups. This
is equivalent to 40% of the SNPs studied.
TABLE I
Observed allele frequencies
SNP Allele
Sick
population
Healthy
population
EXON 11
A>C
C 0.0469 0.0769
A 0.9531 0.9231
EXON 11
A>G
A 0.6094 0.6154
G 0.3906 0.3846
EXON 11
A>indel
A 1.0000 1.0000
- 00000 00000
EXON 11
A>C1
A 1.0000 1.0000
C1 00000 00000
EXON 11
A>C2
A 1.0000 1.0000
C2 00000 00000
EXON 11
A>C3
C3 0.2813 0.1923
A 0.7188 0.8077
EXON 11
A>G1
A 0.9688 0.8846
G1 0.0313 0.1154
EXON 11
A>G2
G2 1.0000 1.0000
A 00000 00000
EXON 11
A>G3
A 0.9688 0.8846
G3 0.0313 0.1154
EXON 11
C>T
T 1.0000 1.0000
C 00000 00000
EXON 22
GAGA>indel
GAGA 1.0000 1.0000
- 00000 00000
EXON 23
AG>indel
AG 1.0000 1.0000
- 00000 00000
EXON 23
C>T
C 0.0313 0.0769
T 0.9688 0.9231
EXON 27
A>G
G 1.0000 1.0000
A 00000 00000
EXON 27
TG>indel
TG 1.0000 1.0000
- 00000 00000
SNPs with polymorphisms are shown in red
FIGURE 1. Three-dimensional graphical representation of the correspondence factor analysis. In this image, once more it is seen how individuals
from both populations studied are admixed, with no subdivisions between them. The results are shown in yellow (dogs with tumours) and
in blue (dogs without tumours)
BRCA1 and BRCA2 genes in dogs / Decuadro et al. _________________________________________________________________________________
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Chi-Square test for analysis of Hardy Weinberg equilibrium (H&W)
In order to know whether the analyzed loci were or not in H&W
equilibrium, it was performed a chi-square test for each of them
in both populations. TABLE II shows these results. In the case
of monomorphic loci, all of them were in disequilibrium, with
chi-square values greater than 10.83; that is, P≤0.001. Of the loci
with polymorphism, two were in disequilibrium [19].
Correspondence factor analysis
It was performed a correspondence factor analysis in both
populations (with and without tumors) for the six polymorphic markers.
It was used the GENETIX V 4.05 program to construct the gure (FIG. 1).
In summary, regarding the genetic study of the 15 loci, six were
polymorphic (40%), all of them of the SNP type, while the other nine
were monomorphic (with no variation). It was obtained a low allelic
variability, but at the population level the tumor group has greater
variability than the control group. On the other hand, the different
analyses of possible groupings (dendrograms, correspondence factorial
analysis) were negative, and it was not possible to clearly dene groups
with the parameters it was used.
In dogs, there is evidence that changes in the BRCA1 and BRCA2 genes
are associated with mammary tumors, just like in humans. Mutations
in these genes can be used both for diagnosis and treatment of breast
tumors and to further advance cancer treatment in Veterinary Oncology.
In this work, it was performed different analyzes with polymorphisms of
the BRCA1 and BRCA2 genes. In rst place, the fact that most of them
are in H&W disequilibrium may be due to different elements, among
them the fact that they are part of the sequence of the same exon in
each of the studied genes (BRCA1 and BRCA2).
On the other hand, there is the possibility that there is some
evolutionary force on them. It should be taken into account that pure
bred animals have been subjected to an intense selection by man,
which could indirectly generate imbalances in allelic frequencies. In
the case of dogs, there is a stronger concern regarding whether there
is sucient mating within breeds, because they have developed over
the past 150 years by selective breeding of animals with desirable
phenotypic traits.
Breed development begins with a small founder population, usually
two or four dogs that have such traits. The population grows from
mattings of related animals, this leads to dogs of a given breed having
a common genetic base. Selection by desirable phenotypic traits
has resulted in latent selection of hereditary and genetically-based
diseases, as well as predisposition to certain pathologies. Today, some
TABLE II
Chi-square values obtained for loci with observed
polymorphisms.
Locus
With tumors No tumors
Χ
2
P Χ
2
P
EXON 11 A>C 0.08 ≥ 0.70 0.09 ≥ 0.70
EXON 11 A>G 0.69 ≥ 0.30 0.01 ≥ 0.90
EXON 11 A>C3 0.22 ≥ 0.50 0.75 ≥ 0.30
EXON 11 A>G1 0.04 ≥ 0.80 4.94 < 0.01
EXON 11 A>G3 0.04 ≥ 0.80 4.94 < 0.01
EXON 23 C>T 0.04 ≥ 0.80 0.09 ≥ 0.70
The two loci with no H&W equilibrium are shown in red
F
IS
, F
IT
and F
ST
values
It was calculated F
IS
, F
IT
and F
ST
. The results obtained were 0.07681,
0.06800 and 0.00954, respectively, it can be seen that there is no
subdivision among the animals studied, which is another way to see
what was previously mentioned.
In particular, with regard to the F
IS
values, positive values were found
in both populations, which would indicate a decit of heterozygotes
or excess of homozygotes, which again agrees with the genotyping
results obtained.
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breeds have a high incidence of certain diseases. Breed specicity
in this regard makes dogs ideal candidates for comparative genetic
association studies; however, it should be considered that most of
the breeds would be too inbred to be used in this type of case-control
association studies [18].
In this study, population’s F
IS
values were positive but low, thus
indicating a decit of heterozygotes or an excess of homozygotes,
although there was allelic variability, which once more agrees with
the genotyping results obtained where only six of the 15 markers
studied showed polymorphism. In any case, it is interesting that,
in the population with tumors, the F
IS
is lower than in the control
population (0.03876, which is a positive value but nevertheless low,
that is, towards heterozygosis, while 0.15353 is positive and high,
towards homozygosis), which means that there is greater genetic
variability in the population with tumors. In this regard, one of the
elements to be considered is the number of animals in each group (32
with tumors, and 13 without tumors), where it would be important to
form groups with more similar sizes. Besides this, another fact that
we must consider is the admixture of breeds in each group [6, 12].
CONCLUSIONS
The data presented in the analysis carried out here may be due to
numerous factors such as inherent characteristics of the populations
studied, as the size of both populations; the breeds studied; tumor
diversity. For this reason, it was intended to homogenize the working
groups in these aspects.
The genes studied in this work have been widely related to breast
cancer, both in humans and in dogs. In the former, they have been
highly implicated in hereditary tumors. In the present case, it was
no found relationship between each of the markers studied and the
occurrence of mammary tumor between the problem group and the
control group. For this reason, in addition to the above, and because
it do not have hereditary/non-hereditary data of this species, it was
intend to increase the spectrum of genes studied in order to nd
markers useful in different aspects of clinical oncology, as well as
starting to carry out family studies with the aim of analyzing the
hereditary component.
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