Abstract
Genomic and precision medicine research has afforded notable advances in human cancer treatment, yet applicability to other species remains uncertain. Through whole-exome and transcriptome analyses of 191 spontaneous canine mammary tumors (CMTs) that exhibit the archetypal features of human breast cancers, we found a striking resemblance of genomic characteristics including frequent PIK3CA mutations (43.1%), aberrations of the PI3K-Akt pathway (61.7%), and key genes involved in cancer initiation and progression. We also identified three gene expression-based CMT subtypes, one of which segregated with basal-like human breast cancer subtypes with activated epithelial-to-mesenchymal transition, low claudin expression, and unfavorable disease prognosis. A relative lack of ERBB2 amplification and Her2-enrichment subtype in CMT denoted species-specific molecular mechanisms. Taken together, our results elucidate cross-species oncogenic signatures for a better understanding of universal and context-dependent mechanisms in breast cancer development and provide a basis for precision diagnostics and therapeutics for domestic dogs.
Highlights
Genomic and precision medicine research has afforded notable advances in human cancer treatment, yet applicability to other species remains uncertain
We show a notable similarity between canine mammary tumors (CMTs) and human breast cancers in terms of recurrent aberration in oncogenic pathways, which suggests molecular convergence of carcinogenesis, and highlight a number of novel CMT-specific mutations and their effects on tumor characteristics
The most frequent histologic type in the cohort was simple carcinoma, 63% (49/78) of which were of tubulopapillary type, resembling the natural incidence of malignant CMT8
Summary
Genomic and precision medicine research has afforded notable advances in human cancer treatment, yet applicability to other species remains uncertain. Calls for a deeper understanding of the molecular characteristics of CMTs are growing in order to uncover crossspecies hallmarks of cancer and to provide better opportunities for treating cancers in dogs Despite their apparent similarities, CMTs and human breast cancers show molecular and histological discrepancies that have perplexed veterinary and cancer researchers. Tumors with mesenchymal origins (e.g., fibrosarcomas and carcinosarcomas) and proliferation of myoepithelial cells (e.g., complex adenomas/carcinomas) are often found in CMTs, all of which are extremely rare in human breast cancers[12] These observations may imply the presence of distinctive mechanisms underlying carcinogenesis and cancer progression in and the need for morespecified therapeutic strategies for CMTs. Several studies have attempted to advance understanding of the genetic landscape underlying CMTs. Beck et al.[13] documented CMT-specific gene fusions and deletions using low-depth genome sequencing of five cases. We presumed that multi-omics profiling of CMTs in a large cohort, as in research into human cancers, would lead to better understanding of the underlying molecular pathogenesis of CMTs and inter-species relationships with human cancer
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