Canine mammary tumors as a comparative model for human breast cancer

Mammary tumors in dogs hold great potential as naturally occurring breast cancer models in translational oncology, as they share the same environmental risk factors, key histological features, hormone receptor expression patterns, prognostic factors, and genetic characteristics as their human counterparts. We aimed to investigate canine mammary tumors genetic characteristics (CMT) and we performed WGS on 21 malignant CMT derived from 17 patients.By comparing the tumor sample and matched normal sample, we found that mutations of PIK3CA are the most frequent (6/21) and they occur at known hot spots (H1047R, G118D, R108Q) in HBC and CMT, leading to activation of the PI3K-AKT pathway. Further downstream in this signaling pathway, we found mutations of AKT1 with the E17K hotspot shared both by humans and dogs. This indicates that the activation of the PI3K-AKT pathway plays a fundamental role in the tumorigenesis of several CMT, similar to part of the HBC.We then examined mutational signatures present in this cohort, which revealed mutational signature 1 (from the COSMIC mutational signature catalog) in nearly all CMT (17/21 cases). This signature related to age at diagnosis, is also present in HBC and many other cancer types.However, our analysis revealed substantial differences in the mutational landscape of CMT compared to HBC. Although the number of samples is limited (n=21), it clearly shows that the number of mutations is much lower in CMT. Moreover, HER2 amplifications are not observed, and several mutational signatures frequently present in HBC, such as the ones resulting from defects in APOBEC cytidine deaminases or homologous recombination repair deficiency, are very rare in CMT. Instead, age-related deamination of methyl cytosines seems to be the dominant genotype. With the available data, no novel dog-specific MS were detected.