Molecular Parallelisms and Divergences Between Human and Canine Cancers Would a dog be an appropriate experimental model for human cancers?

Abstract

Canine mammary cancer is poorly characterized at the genomic level. Dog really can be an appropriate experimental model for human cancers from the genomic and evolutionary perspective or not? Here, we perform a cross-species cancer genomics analysis, independent evolution of cancer from normal tissues, which provide us an excellent opportunity to address an evolutionary perspective of cancer. As, evolutionary theories are critical for understanding tumorigenesis at the level of species as well as at the level of cells and tissues, for the development of effective therapies. Analysis of canine mammary cancer reveals a diversity of histological types as compare to human breast cancer. Our systematic analysis of 24 canine mammary tumors with whole-genome sequences, reveals 185 protein-coding cancer genes carried exonic mutations. Cross-species comparative analysis of 1080 human breast cancers identifies higher median mutation frequency in human breast cancer and canine mammary cancer shows lower across exonic regions (2.67 and 0.187 average no. of mutations per tumor per megabase (Mb), respectively). A comparison of somatic mutations in the PIK3CA gene, reveals common recurrence of the conserved mutations, in both species. However, the Ka/Ks ratio in the human PIK3CA gene 2.37 is higher and 1.43 in dogs is lower. To address the mutation accumulation and antagonistic pleiotropy theory, we investigated Ka/Ks value 237 aging-related genes from human and canine, the aging-related genes do not show selection in canine mammary cancer. It demonstrates new aspects of cancer genes that are evolving in different species instantaneously. These findings may suggest, the same organs in different mammals impose different selective pressures on the same set of genes in cancer. In both species, some genes may experience strong selective pressures, but do not converge genetically or the conserved genes do not show the same selection pressure in both species. However, human breast cancer shows transcriptomic similarity with canine mammary carcinoma but the other subtypes are quite different. We found canine mammary tumor can be used as a model for inter and intra-tumor heterogeneity. These findings provided insight into mammary cancer across species and possessed potential clinical significance. Collectively, these studies suggest a convergence of some genetic changes in mammary cancer between species but also distinctly different paths to tumorigenesis.