Genetic variations of BRCA1 and BRCA2 genes in dogs with mammary tumours

Abstract

Mammary tumours are the most common tumour type in female dogs. The formation of the mammary tumours is multifactorial but the high incidence of tumour disease in certain canine breeds suggests a strong genetic component. BRCA1 and BRCA2 are the most important genes significantly associated with mammary tumours. The aim of this study was to determine the association between the variations of these two genes and canine mammary tumours. 5'-untranslated region, intron 8 and exon 9 of BRCA1 and exons 12, 24, 27 of BRCA2 were sequenced in order to detect the genetic variations. In addition to six previously identified polymorphisms, six novel single nucleotide polymorphisms (SNPs) were detected. Five of the coding SNPs were synonymous and three of them were non-synonymous. The comparison of the sequences from 25 mammary tumour bearing and 10 tumour free dogs suggested that the two SNPs in intron 8 and exon 9 of BRCA1 and two SNPs in exon 24 and exon 27 of BRCA2, which are firstly identified in this study, might be associated with mammary tumour development in dogs. Especially one SNP in exon 9 of BRCA1 and one SNP in exon 24 of BRCA2 were found to be significantly associated with canine mammary tumours.

Comparative oncology: what dogs and other species can teach us about humans with cancer

“…High-risk breeds of dog can be thought of as if they carry a hereditary cancer syndrome, although breed-specific screening in asymptomatic dogs has not yet become standard of care. Interestingly, several of the human cancer predisposition genes have been found in the constitutional (germline) DNA of dogs with cancer; this includes BRCA1/BRCA2 germline mutations in dogs [30,31] which leads to hereditary breast and ovarian cancer syndrome in humans and TP53 germline mutations in dogs [32] which lead to Li-Fraumeni syndrome in humans with multiple different cancers.…”

<b>Polymorphisms of canine BRCA2 BRC repeats affecting interaction with </b><b>RAD51 </b>

“…Mammary tumors are the most common neoplasia in female dogs, and are highly prevalent in certain dog breeds (17). It has been reported that BRCA2 mutations are associated with the development of mammary tumors in dogs (4,12). We cloned and sequenced canine BRCA2 and found polymorphisms in the putative functional regions containing BRC repeats and nuclear localization signals (8,19).…”

A monograph proposing the use of canine mammary tumours as a model for the study of hereditary breast cancer susceptibility genes in humans

“…; Enginler et al . ); in fact, a subsequent paper by Yoshikawa et al . () reported the variant to be neutral.…”

“…Ultimately, the presence of p.M3332IK reported a slightly stronger BRCA2/Rad51 interaction, which could disturb the transfer of Rad51 to its substrate, leading to the authors' pathogenicity prediction (Yoshikawa et al 2005). Despite the fact that this variant has been reported in additional sequencing studies that aimed to identify germline CMT-risk variants (Table 1), no associations could be claimed (Borge et al 2011;Enginler et al 2014); in fact, a subsequent paper by Yoshikawa et al (2012) reported the variant to be neutral. Rivera et al (2009) were the first to report an association between CMT and variants in BRCA1 and BRCA2.…”

“…1) had thus far returned goading variant profiles. Thus, the next case-control study surveyed female dogs (25 with and 10 without a CMT diagnosis) from a variety of breeds for genetic differences specifically in BRCA1 and BRCA2 (Enginler et al 2014). Clinical information such as age, age at spaying or intact status, tumour histopathology, body weight and breed were all noted.…”