Abstract
BackgroundAlthough, in general, cancer is considered a multifactorial disease, clustering of particular cancers in pedigrees suggests a genetic predisposition and could explain why some dog breeds appear to have an increased risk of certain cancers. To our knowledge, there have been no published reports of whole genome sequencing to investigate inherited canine mammary tumor (CMT) risk, and with little known about CMT genetic susceptibility, we carried out whole genome sequencing on 14 purebred dogs diagnosed with mammary tumors from four breed-specific pedigrees. Following sequencing, each dog’s data was processed through a bioinformatics pipeline. This initial report highlights variants in orthologs of human breast cancer susceptibility genes.ResultsThe overall whole genome and exome coverage averages were 26.0X and 25.6X, respectively, with 96.1% of the genome and 96.7% of the exome covered at least 10X. Of the average 7.9 million variants per dog, initial analyses involved surveying variants in orthologs of human breast cancer susceptibility genes, BRCA1, BRCA2, CDH1, PTEN, STK11, and TP53, and identified 19 unique coding variants that were validated through PCR and Sanger sequencing. Statistical analyses identified variants in BRCA2 and STK11 that appear to be associated with CMT, and breed-specific analyses revealed the breeds at the highest risk. Several additional BRCA2 variants showed trends toward significance, but have conflicting interpretations of pathogenicity, and correspond to variants of unknown significance in humans, which require further investigation. Variants in other genes were noted but did not appear to be associated with disease.ConclusionsWhole genome sequencing proves to be an effective method to elucidate risk of CMT. Risk variants in orthologs of human breast cancer susceptibility genes have been identified. Ultimately, these whole genome sequencing efforts have provided a plethora of data that can also be assessed for novel discovery and have the potential to lead to breakthroughs in canine and human research through comparative analyses.
Highlights
In general, cancer is considered a multifactorial disease, clustering of particular cancers in pedigrees suggests a genetic predisposition and could explain why some dog breeds appear to have an increased risk of certain cancers
Risk variants in orthologs of human breast cancer susceptibility genes have been identified. These whole genome sequencing efforts have provided a plethora of data that can be assessed for novel discovery and have the potential to lead to breakthroughs in canine and human research through comparative analyses
Plain ENGLISH summary Despite the advances in sequencing technology and the success of previous canine whole genome sequencing research, we know of no other publications that report using whole genome sequencing to investigate a genetic risk for canine mammary tumors in purebred dogs
Summary
In general, cancer is considered a multifactorial disease, clustering of particular cancers in pedigrees suggests a genetic predisposition and could explain why some dog breeds appear to have an increased risk of certain cancers. Each dog’s data was processed through a bioinformatics pipeline This initial report highlights variants in orthologs of human breast cancer susceptibility genes. Since investigating hereditary diseases that segregate in purebred lines/pedigrees have fostered numerous genetic discoveries; over 130 canine hereditary diseases are genetically explained [2,3,4]. Through these discoveries, it has been determined that there is much genetic overlap between canine and human disease. The elucidation of certain hereditary canine diseases has even led to breakthroughs in human medicine, with diseases such as sleep disorders, Birt-Hogg-Dubé syndrome, and more [3, 6,7,8,9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
