Molecular Biological Aspects on Canine and Human Mammary Tumors (original) (raw)
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Genome-Wide Analysis Identifies Germ-Line Risk Factors Associated with Canine Mammary Tumours
PLoS genetics, 2016
Canine mammary tumours (CMT) are the most common neoplasia in unspayed female dogs. CMTs are suitable naturally occurring models for human breast cancer and share many characteristics, indicating that the genetic causes could also be shared. We have performed a genome-wide association study (GWAS) in English Springer Spaniel dogs and identified a genome-wide significant locus on chromosome 11 (praw = 5.6x10-7, pperm = 0.019). The most associated haplotype spans a 446 kb region overlapping the CDK5RAP2 gene. The CDK5RAP2 protein has a function in cell cycle regulation and could potentially have an impact on response to chemotherapy treatment. Two additional loci, both on chromosome 27, were nominally associated (praw = 1.97x10-5 and praw = 8.30x10-6). The three loci explain 28.1±10.0% of the phenotypic variation seen in the cohort, whereas the top ten associated regions account for 38.2±10.8% of the risk. Furthermore, the ten GWAS loci and regions with reduced genetic variability are...
Worldwide, canine mammary cancer (CMC) is the most frequent type of neoplasia in female dogs, and it is three times more frequent in dogs than in humans. In Colombia, CMC is the second most frequent type of cancer, after skin neoplasia. Genetics is one of the most important factors involved in any type of cancer, and the genetic basis of this disease is reflected through line breeding due to changes in allelic frequencies that are traceable using molecular markers. This study aimed to detect single nucleotide polymorphisms (SNPs) associated with CMC in blood samples collected from collected from healthy and CMC female dogs at
Molecular homology and difference between spontaneous canine mammary cancer and human breast cancer
Cancer research, 2014
Spontaneously occurring canine mammary cancer represents an excellent model of human breast cancer, but is greatly understudied. To better use this valuable resource, we performed whole-genome sequencing, whole-exome sequencing, RNA-seq, and/or high-density arrays on twelve canine mammary cancer cases, including seven simple carcinomas and four complex carcinomas. Canine simple carcinomas, which histologically match human breast carcinomas, harbor extensive genomic aberrations, many of which faithfully recapitulate key features of human breast cancer. Canine complex carcinomas, which are characterized by proliferation of both luminal and myoepithelial cells and are rare in human breast cancer, seem to lack genomic abnormalities. Instead, these tumors have about 35 chromatin-modification genes downregulated and are abnormally enriched with active histone modification H4-acetylation, whereas aberrantly depleted with repressive histone modification H3K9me3. Our findings indicate the li...
Canine mammary tumor risk is associated with polymorphisms in RAD51 and STK11 genes
Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc, 2018
Cancer is a complex disease involving genetic and phenotypic changes. Several single nucleotide polymorphisms (SNPs) have been associated with the risk of breast cancer development in women; however, little is known regarding their influence on canine mammary tumor risk. We assessed the influence of SNPs in genes related to human breast cancer susceptibility, with respect to the risk of development of mammary tumors in dogs. Sixty-seven canine SNPs in proto-oncogenes, tumor suppressor genes, genes involved in DNA repair, and in hormonal metabolism were evaluated in 212 bitches with mammary tumors and in 161 bitches free of mammary neoplasia. A significant association with mammary neoplasia risk was identified for 2 SNPs in RAD51 ( rs23623251 and rs23642734) and one SNP in the STK11 gene ( rs22928814). None of the other SNPs were related to the risk of mammary tumor development. The identification of genetic profiles associated with risk of mammary neoplasia is of great importance, s...
Cross-species oncogenic signatures of breast cancer in canine mammary tumors
Nature Communications
Genomic and precision medicine research has afforded notable advances in human cancer treatment, yet applicability to other species remains uncertain. Through whole-exome and transcriptome analyses of 191 spontaneous canine mammary tumors (CMTs) that exhibit the archetypal features of human breast cancers, we found a striking resemblance of genomic characteristics including frequent PIK3CA mutations (43.1%), aberrations of the PI3K-Akt pathway (61.7%), and key genes involved in cancer initiation and progression. We also identified three gene expression-based CMT subtypes, one of which segregated with basal-like human breast cancer subtypes with activated epithelial-to-mesenchymal transition, low claudin expression, and unfavorable disease prognosis. A relative lack of ERBB2 amplification and Her2-enrichment subtype in CMT denoted species-specific molecular mechanisms. Taken together, our results elucidate cross-species oncogenic signatures for a better understanding of universal and...
Whole-exome and whole-transcriptome sequencing of canine mammary gland tumors
Scientific Data, 2019
Studies of naturally occurring cancers in dogs, which share many genetic and environmental factors with humans, provide valuable information as a comparative model for studying the mechanisms of human cancer pathogenesis. While individual and small-scale studies of canine cancers are underway, more generalized multi-omics studies have not been attempted due to the lack of large-scale and well-controlled genomic data. Here, we produced reliable whole-exome and whole-transcriptome sequencing data of 197 canine mammary cancers and their matched controls, annotated with rich clinical and biological features. Our dataset provides useful reference points for comparative analysis with human cancers and for developing novel diagnostic and therapeutic technologies for cancers in pet dogs.
Association of A4304G in exon eleven of Brca2 gene with canine mammary tumour
Journal of Veterinary and Animal Sciences
Canine mammary tumour is one among the prevalent life style diseases affecting dogs. Certain breeds of dogs are predisposed to mammary neoplasia indicating a possible role of genetic factors in the incidence of disease. Several candidate genes have been studied for its association with mammary tumour in dogs, of which Breast Cancer 2 is one among the genes responsible for the mammary tumour in dogs. In the current study, A4304G within exon 11 of Breast Cancer 2 gene was evaluated for its association with canine mammary tumour. The whole genomic DNA was extracted from 100 female dogs (50 mammary tumour affected dogs and 50 normal animals) above five years. Polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) confirmed the presence of the concerned polymorphism among the 100 female dogs under study. On statistical analysis a significant association of the missense variant A4304G with mammary tumour could not be obtained.
Partial sequencing of ESR1 and CDK5RAP2 genes in dogs with mammary tumours
Indian Journal of Animal Research
Canine mammary tumours (CMT) are among the most common canine cancer types in female dogs. Dogs provide an adaptable model system for human breast cancer studies. It is important to identify the underlying genetic basis to improve knowledge of pathways related to cancer pathogenesis in both species. In this study, we investigated CMT associated single nucleotide polymorphisms (SNP) in target regions of ESR1 and CDK5RAP2 genes. Partial sequencing of two genes in 25 cases with mammary tumours and 10 dogs with healthy mammary glands was performed. Two previously reported SNPs in ESR1 gene and one previously reported SNP and two novel SNPs were genotyped downstream CDK5RAP2 gene. According to the association analysis performed in cases and controls, no statistically significant association was found between these SNPs and CMTs. Comparison of the results from other studies revealed the genetic heterogeneity of ESR1 and CDK5RAP2 between different dog breeds. Larger datasets of different b...
The ESR1 gene is associated with risk for canine mammary tumours
BMC Veterinary Research, 2013
Background: The limited within-breed genetic heterogeneity and an enrichment of disease-predisposing alleles have made the dog a very suitable model for the identification of genes associated with risk for specific diseases. Canine mammary cancer is an example of such a disease. However, the underlying inherited risk factors for canine mammary tumours (CMTs) are still largely unknown. In this study, 52 single nucleotide polymorphisms (SNPs) in ten human cancer-associated genes were genotyped in two different datasets in order to identify genes/alleles associated with the development of CMTs. The first dataset consisted of English Springer Spaniel (ESS) CMT cases and controls. ESS is a dog breed known to be at increased risk of developing CMTs. In the second dataset, dogs from breeds known to have a high frequency of CMTs were compared to dogs from breeds with a lower occurrence of these tumours. Results: We found significant associations to CMT for SNPs and haplotypes in the estrogen receptor 1 (ESR1) gene in the ESS material (best P Bonf = 0.021). A large number of SNPs, among them several SNPs in ESR1, showed significantly different allele frequencies between the high and low risk breed groups (best P Bonf = 8.8E-32, best P BPerm = 0.076). Conclusions: The identification of CMT-associated SNPs in ESR1 in two independent datasets suggests that this gene might be involved in CMT development. These findings also support that CMT may serve as a good model for human breast cancer research.