Somatic <scp>SNPs</scp> of the <i><scp>BRCA2</scp></i> gene at the fragments encoding <i><scp>RAD51</scp></i> binding sites of canine mammary tumors

Özmen, Özge; Kul, Selim; Rişvanlı, Ali; Özalp, G. R.; Sabuncu, Ahmet; Kul, Oğuz

doi:10.1111/vco.12293

Cited by 15 publications

(34 citation statements)

References 27 publications

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“…Studies of in vitro and in vivo assays demonstrated that canine BRCA2 mutations located in BRC3 do affect interactions with RAD51. Similarly as their corresponding human BRCA2 variants (p.T1430P and p.K1440R), the SNPs in BRC3 domain of canine BRCA2 (p.T1425P and p.K1435R) also showed to affect the interaction with the RAD51 protein . The canine BRCA2 polymorphism that result in amino acid change p.T1425P showed evidences of reducing the binding strength with RAD51 and probably affect the full‐length of BRC functions.…”

Section: Discussionmentioning

confidence: 96%

“…Differently, the canine BRCA2 polymorphism that result in amino acid change p.K1435R, as well as its analogous human variant p.K1440R, revealed stronger interactions with canine RAD51 and human RAD51, inhibiting RAD51 self association to a greater extent than the wild‐type BRC3. Therefore, it is suggested that these mutations in dogs and humans might be associated to mammary tumors as a result of their effect on the regulation of RAD51 recruitment …”

Section: Discussionmentioning

confidence: 99%

“…Some genetic variants that are located in strongly conserved regions of the gene is more likely to be disease‐associated than polymorphisms occurring in regions with a lower degree of conservation . In this context, the variant p.K801Q was identified as a damaging variant by other authors and showed to have a deleterious effect by PolyPhen‐2 and PROVEAN algorithms used to predict functional effects of mutations.…”

Section: Discussionmentioning

confidence: 99%

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

Maués

El-Jaick

Costa

et al. 2018

Vet Comparative Oncology

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Funding informationCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) of the Brazilian Ministry of Education The canine BRCA2 is a tumor supressor gene which encodes the BRCA2 protein, involved in DNA repair through interaction with the RAD51 recombinase. This process is mediated by eigth BRC repeats that are encoded by BRCA2 exon 11. Two variants corresponding to human mutations in human BRC3 repeat have been reported in canine BRC3 repeat. In addition, other variants have also been described in canine BRCA2 exon 11. Considering the importance of polymorphisms in human BRCA2 to breast cancer development, this study aimed to investigate the frequency of variants in BRCA2 exon 11 in 48 blood and tissue DNA samples from bitches with canine mammary tumors (CMT), as well as, to analyze tumor stage and histopathological features. Seven Single Nucleotide Polymorphisms (SNPs) were identified, three of which were evaluated as possibily or probably deleterious variant.Interestingly, almost all the 22 mammary tumors (except one) which presented a clinical staging equal to or greater than III carried at least one mutant allele of these three variants.Besides that, no statistically significant correlation was observed between any of the reported SNPs in heterozygosis or homozygosis and either dogs data (such as breed, age or disease stage) or mammary tumors histopathological characteristics. A total of 97.9% of bitches had one to three polymorphisms of the seven identified in this study, which suggests a possibly correlation between the canine BRCA2 exon 11 polymorphisms and mammary carcinogenesis. K E Y W O R D SBRCA2, breast cancer, canine, carcinogenesis, RAD51

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Maués

El-Jaick

Costa

et al. 2018

Vet Comparative Oncology

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“…In addition, they later analyzed polymorphisms in canine BRC3 and in dogs of multiple breeds: they showed significant reduction of binding strength of BRC3-4 containing the a specific allele version (1425P) with RAD51 (all following polymorphisms summarized in Table 2) [53]. More recently, Ozmen et al investigated the sequence variations of BRC1-BRC8 and Cterminus of canine BRCA2 [54] and found multiple SNPs in exon 11 and one insertion/deletion polymorphism in exon 27. Further in silico investigations added to speculation that a specific variation in BRC3 is the most likely to affect the RAD51 binding strength.…”

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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“…In canine studies, although several mutations have been detected in BRCA2, canine RAD51 (cRAD51) mutations have not been reported. However, a recent report identified the presence of multiple cRAD51 mutations in canine mammary tumours, and predicted that A209S and T225S mutations in cRAD51 might influence its interactions with the “partner and localizer of BRCA2” (PALB2).…”

Section: Introductionmentioning

confidence: 99%

The canine RAD51 mutation leads to the attenuation of interaction with PALB2

Uemura

Ochiai

Morimatsu

et al. 2019

Vet Comparative Oncology

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RAD51 forms a complex with BRCA2 and plays a central role in the DNA damage response pathway that is associated with homologous recombination. The structures of RAD51 and its homologues are highly conserved from prokaryotes to higher eukaryotes. Although a large number of BRCA2 mutations have been reported, there are only a few reports on the mutations of RAD51, which have been shown in humans and dogs. However, several mutations of canine RAD51 were identified from mammary gland tumour tissues in a recent study. Some of these mutations seem to have an influence on the homo-oligomerization or interaction with "Partner and localizer of BRCA2" (PALB2). In this study, we cloned the canine PALB2 homologue and investigated the effect on its interaction with the RAD51 mutants to evaluate the alteration in the function of RAD51 mutants. The A209S and T225S mutants of RAD51 show an attenuation of the interaction between RAD51 and PALB2. These results indicate that the canine RAD51 mutations can potentially alter the homologous recombination pathways in response to DNA damage in dogs. K E Y W O R D SBRCA2, cancer-associated single nucleotide polymorphisms (SNPs), DNA double-strand breaks (DSB), homologous recombination (HR), mammary gland tumour

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Somatic SNPs of the BRCA2 gene at the fragments encoding RAD51 binding sites of canine mammary tumors

Cited by 15 publications

References 27 publications

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

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

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

The canine RAD51 mutation leads to the attenuation of interaction with PALB2

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