Abstract
Mammary tumors are the most frequent cancers in female dogs exhibiting a variety of histopathological differences. There is lack of knowledge about the genomes of these common dog tumors. Five tumors of three different histological subtypes were evaluated. Massive parallel sequencing (MPS) was performed in comparison to the respective somatic genome of each animal. Copy number and structural aberrations were validated using droplet digital PCR (ddPCR). Using mate-pair sequencing chromosomal aneuploidies were found in two tumors, frequent smaller deletions were found in one, inter-chromosomal fusions in one other, whereas one tumor was almost normal. These aberrations affect several known cancer associated genes such as cMYC, and KIT. One common deletion of the proximal end of CFA27, harboring the tumor suppressor gene PFDN5 was detected in four tumors. Using ddPCR, this deletion was validated and detected in 50% of tumors (N = 20). Breakpoint specific dPCRs were established for four tumors and tumor specific cell-free DNA (cfDNA) was detected in the plasma. In one animal tumor-specific cfDNA was found >1 year after surgery, attributable to a lung metastasis. Paired-end sequencing proved that copy-number imbalances of the tumor are reflected by the cfDNA. This report on chromosomal instability of canine mammary cancers reveals similarities to human breast cancers as well as special canine alterations. This animal model provides a framework for using MPS for screening for individual cancer biomarkers with cost effective confirmation and monitoring using ddPCR. The possibility exists that ddPCR can be expanded to screening for common cancer related variants.
Highlights
The most common neoplasms in female dogs are mammary tumors representing more than 40% of all tumors diagnosed [1,2]
Tumors were surgically removed and the diagnosis was confirmed by histological evaluation and additional 15 samples were analyzed by droplet digital PCR (ddPCR)
An ethical approval was not necessary according to the German Tierschutzgesetz (17), because all samples were obtained as part of routine diagnostic procedures and with informed owner consent; tumor samples were obtained by a veterinarian during the medically necessary surgeries
Summary
The most common neoplasms in female dogs are mammary tumors representing more than 40% of all tumors diagnosed [1,2]. An incidence rate of approximately 200/100,000 dogs/ year is reported in studies conducted in the UK and Italy [3,4,5]. In our own three-year clinical study an annual incidence rate of ,1% in a cohort of 9,265 dogs, which were presented as patients in the Clinic for Small Animals in Goettingen, Germany, was calculated. Most mammary tumors in dogs are of epithelial origin, some consist of epithelial and myoepithelial tissues, termed complex carcinomas. Fewer tumors are of mesenchymal origin (e.g. osteosarcomas or fibrosarcomas), which frequently contain epithelial tissues (carcinosarcoma) [2]
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