20P - Molecular parallelisms and divergences between human and canine cancers

Background

Tumorigenesis has been widely accepted as an evolutionary process that comprises two stages of evolution between tumors and normal tissues (Stage I) and within tumors (Stage II) ¹. Patterns of mutation and natural selection, the predominant evolutionary driver forces, vary at the two stages based on the evidence of low genetic convergence among different cancer cases revealed by The Cancer Genome Atlas (TCGA) data and of extremely high intra-tumor genetic diversity measured in high-density sampling studies (Ling et al. 2015; Sottoriva et al. 2015). At Stage, I, positive and negative selection may both exist but neatly counteract in absence of recombination, presenting a plausible neutrality 1, whereas non-Darwinian (neutral) selection was increasingly supported at Stage II by the high-density sampling studies and comparatively genomic and transcriptional distances among distinct normal and cancerous cell populations. Deciphering the evolutionary patterns during tumorigenesis such as selectivity or neutrality, adaptive convergence, or divergence is of both theoretical and clinical significance. Cross-species cancer genomics, independent evolution from normal tissues, provide an excellent opportunity to address this long-standing issue: Does selection drive cancer evolution along with a relatively deterministic (selectivity) or contingent (neutrality) way across species?

Methods

GATAK pipeline and Mutect2.

Results

We performed whole-genome sequencing analysis by using GATAK pipeline and Mutect2 for twenty-four dog mammary cancers and identified 47715 somatic mutations comprising 210 exonic mutations. Comparison between human and dog reveals similarities and differences in the mutation profiles across both species, in terms of the mutated driver genes and mutation number, which are likely to influence tumor behavior and response to treatments. Human breast cancer had a higher median mutation burden comparable to canine mammary cancer, in exonic regions (2.67 and 0.187 average no. of mutations per tumor per megabase (Mb), respectively).

Conclusions

Taken together, for the first time, we reported canine mammary tumors comprising mutated genes, mutation burden, mutational patterns, spectrums, and signatures at the whole genome level.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The author.

Funding

CAS-TWAS.

Disclosure

The author has declared no conflicts of interest.