Common germline haplotypes and genotypes identified in <i>BRCA2</i> exon 11 of dogs with mammary tumours and histopathological analyses

Maués, Tábata; El-Jaick, Kênia Balbi; Costa, Felipe dos Santos; Araujo, Gabriela Eduardo França de; Soares, Magali; Moreira, Aline dos Santos; Ferreira, Manoel Luiz; Ferreira, Ana Maria Reis

doi:10.1111/vco.12389

Cited by 11 publications

(20 citation statements)

References 25 publications

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“…Single-nucleotide polymorphism analysis of intronic markers in female dogs with mammary tumors has suggested that the canine BRCA2 gene locus is associated with mammary tumors [ 21 ]. Consistent with this notion, we, along with other researchers, have previously demonstrated the presence of loss of heterozygosity, which is one of the mechanisms of canine and human BRCA2 inactivation and tumor-related mutations in mammary tumors [ 1 , 6 , 11 , 15 , 19 , 21 , 24 , 25 ].…”

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confidence: 90%

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Identification of the core motif of the BRCA2 C-terminal RAD51-binding domain by comparing canine and human BRCA2

Yoshikawa

Morimatsu

Ochiai

et al. 2021

The Journal of Veterinary Medical Science

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Mammary tumors are the most common tumors in women and non-spayed female dogs. One of the reasons for mammary tumors is mutations of the tumor suppressor gene, BRCA2. BRCA2 participates in homologous recombination repair by interacting with the RAD51 recombinase. BRCA2 has two RAD51-binding domains, consisting of BRC repeats and the C-terminal RAD51-binding domain, respectively. Although several studies have addressed the function of the C-terminal RAD51-binding domain of human BRCA2, the amino acid sequences required for the RAD51-interaction activity remain unclear. In this study, the C-terminal RAD51-binding domains of canine and human BRCA2 were compared; the canine domain displayed a weaker interaction with RAD51. This difference was attributed to the C-terminal portion of the domain via a comparison between canine and-2 human domains. Furthermore, peptides shorter than those previously reported displayed RAD51-interacting activity, and a core motif of this domain consisting of 25 amino acids was identified. Since a mutation (S3323N) was reported in the core motif of this domain, the effect of this mutation was evaluated. The mutant exhibited similar RAD51-binding activity as that of the wild-type protein, suggesting that the mutation was functionally neutral. These data suggested that the C-terminal portion of the BRCA2 C-terminal RAD51-binding domain influenced its RAD51-interaction activity, and a minimum core motif of 25 amino acids was identified in this domain. These data may help clarify BRCA2 function, as well as the tumorigenic effects of BRCA2 mutation.

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confidence: 90%

“…Several groups have reported BRCA2 mutations in canine mammary tumors [ 1 , 6 , 11 , 15 , 19 , 21 , 24 , 25 ]. One of these (S3323N) was found to be located in the core motif of the C-terminal RAD51-binding domain ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification of the core motif of the BRCA2 C-terminal RAD51-binding domain by comparing canine and human BRCA2

Yoshikawa

Morimatsu

Ochiai

et al. 2021

The Journal of Veterinary Medical Science

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“…This process is mediated by eight BRC repeats that are encoded by BRCA2 exon 11. Maués et al [46] investigated the frequency of variants in BRCA2 exon 11 using 48 blood and tissue DNA samples from CMT. Seven single nucleotide polymorphisms (SNPs) were identified, three of which were evaluated as possibly or probably deleterious variants.…”

Section: Discussionmentioning

confidence: 99%

Liquid Biopsy as a Diagnostic and Prognostic Tool for Women and Female Dogs with Breast Cancer

Colombo

Moschetta-Pinheiro

Novais

et al. 2021

Cancers

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Introduction: Breast cancer (BC) is the malignant neoplasm with the highest mortality rate in women and female dogs are good models to study BC. Objective: We investigated the efficacy of liquid biopsy to detect gene mutations in the diagnosis and follow-up of women and female dogs with BC. Materials and Methods: In this study, 57 and 37 BC samples were collected from women and female dogs, respectively. After core biopsy and plasma samples were collected, the DNA and ctDNA of the tumor fragments and plasma were processed for next generation sequencing (NGS) assay. After preprocessing of the data, they were submitted to the Genome Analysis ToolKit (GATK). Results: In women, 1788 variants were identified in tumor fragments and 221 variants in plasma; 66 variants were simultaneously detected in tumors and plasma. Conversely, in female dogs, 1430 variants were found in plasma and 695 variants in tumor fragments; 59 variants were simultaneously identified in tumors and plasma. The most frequently mutated genes in the tumor fragments of women were USH2A, ATM, and IGF2R; in female dogs, they were USH2A, BRCA2, and RRM2. Plasma of women showed the most frequent genetic variations in the MAP3K1, BRCA1, and GRB7 genes, whereas plasma from female dogs had variations in the NF1, ERBB2, and KRT17 genes. Mutations in the AKT1, PIK3CA, and BRIP genes were associated with tumor recurrence, with a highly pathogenic variant in PIK3CA being particularly prominent. We also detected a gain-of-function mutation in the GRB7, MAP3K1, and MLH1 genes. Conclusion: Liquid biopsy is useful to identify specific genetic variations at the beginning of BC manifestation and may be accompanied over the entire follow-up period, thereby supporting the clinicians in refining interventions.

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“…Maués et al investigated canine BRCA2 exon 11 as well, evaluating the frequency of exon 11 SNPs in bitches with mammary tumors [49]. In their study, 97.9% of the bitches were affected by one to three SNPs in BRCA2 exon 11, suggesting a correlation between these gene polymorphisms and carcinogenesis [49].…”

Section: Polymorphisms Found In the Canine Brca2 Genementioning

confidence: 99%

Mutations of BRCA2 in canine mammary tumors and their targeting potential in clinical therapy

2020

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Dogs develop cancer spontaneously with age, with breed-specific risk underlying differences in genetics. Mammary tumors are reported as the most frequent neoplasia in intact female dogs. Their high prevalence in certain breeds suggests a genetic component, as it is the case in human familial breast cancer, distinctly in BRCA2-associated cancers. However, the molecular genetics of BRCA2 in the pathogenesis of canine cancer are still under investigation. Genetic variations of canine BRCA2 comprised single nucleotide polymorphisms, insertions and deletions. The BRCA2 level has been shown to be reduced in tumor gland samples, suggesting that low expression of BRCA2 is contributing to mammary tumor development in dogs. Additionally, specific variations of the BRCA2 gene affect RAD51 binding strength, critically damage the BRCA2-RAD51 binding and further provoke a defective repair. In humans, preclinical and clinical data revealed a synthetic lethality interaction between BRCA2 mutations and PARP inhibition. PARP inhibitors are successfully used to increase chemo-and radiotherapy sensitivity, although they are also associated with numerous side effects and acquired resistance. Cancer treatment of canine patients could benefit from increased chemo-and radiosensitivity, as their cancer therapy protocols usually include only low doses of drugs or radiation. Early investigations show tolerability of iniparib in dogs. PARP inhibitors also imply higher therapy costs and consequently are less likely to be accepted by pet owners. We summarized the current evidence of canine BRCA2 gene alterations and their association with mammary tumors. Mutations in the canine BRCA2 gene have the potential to be exploited in clinical therapy through the usage of PARP inhibitors. However, further investigations are needed before introducing PARP inhibitors in veterinary clinical practice.

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Common germline haplotypes and genotypes identified in BRCA2 exon 11 of dogs with mammary tumours and histopathological analyses

Cited by 11 publications

References 25 publications

Identification of the core motif of the BRCA2 C-terminal RAD51-binding domain by comparing canine and human BRCA2

Identification of the core motif of the BRCA2 C-terminal RAD51-binding domain by comparing canine and human BRCA2

Liquid Biopsy as a Diagnostic and Prognostic Tool for Women and Female Dogs with Breast Cancer

Mutations of BRCA2 in canine mammary tumors and their targeting potential in clinical therapy

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