Spontaneous canine cancers are valuable but relatively understudied and underutilized models. To enhance their usage, we reanalyze whole exome and genome sequencing data published for 684 cases of >7 common tumor types and >35 breeds, with rigorous quality control and breed validation. Our results indicate that canine tumor alteration landscape is tumor type-dependent, but likely breed-independent. Each tumor type harbors major pathway alterations also found in its human counterpart (e.g., PI3K in mammary tumor and p53 in osteosarcoma). Mammary tumor and glioma have lower tumor mutational burden (TMB) (median < 0.5 mutations per Mb), whereas oral melanoma, osteosarcoma and hemangiosarcoma have higher TMB (median ≥ 1 mutations per Mb). Across tumor types and breeds, TMB is associated with mutation of TP53 but not PIK3CA, the most mutated genes. Golden Retrievers harbor a TMB-associated and osteosarcoma-enriched mutation signature. Here, we provide a snapshot of canine mutations across major tumor types and breeds.

SummaryWhen the assimilation efficiency in batch culture of a variety of heterotrophic bacteria was tested in media containing progressively smaller concentrations of carbon substrate, two groups emerged. Those in the first group assimilated carbon progressively more efficiently as the initial concentration in the culture medium was lowered below 2 mg C/ml: some displaying efficiencies exceeding 80%. Those in the second group assimilated carbon at rates that changed little, if at all, with changes in the initial concentrations of carbon substrate. Members of the second group differed from the first in their metabolic versatility as evidenced by the ability of each to catabolize hydrocarbons. The energy content (heat of combustion) of the cells of the species tested vaned little with changes in cultured conditions, and values for all'fell close to the average for bacteria (5411 cal/g ash-free dry wt). In continuous aerobic culture on glucose-minimal medium, the carbon assimilation and energy assimilation efficiencies were simultaneously maximal for Enrerobacter acvogenes when the input carbon concentration was 0.2004 mgiml and the dilution rate was 0.57. An equation for predicting heat of combustion of cells from knowledge of their C,H,N, and 0 ratios was devised and tested. Precision ranged from +6% to -16%.

Spontaneous canine cancers are a valuable but relatively understudied and underutilized model in cancer research. To enhance their usage, we reanalyzed whole exome sequencing data published for 601 dogs with mammary cancer, osteosarcoma, oral melanoma, lymphoma, glioma or hemangiosarcoma from over 35 breeds, after rigorous quality control, including breed validation. Each cancer type harbors distinct molecular features, with major pathway alterations matching its human counterpart (e.g., PI3K for mammary cancer and p53 for osteosarcoma). On average, mammary cancer and glioma have lower mutation rates (median <0.5 mutation per Mb), whereas oral melanoma, osteosarcoma and hemangiosarcoma have higher mutation rates (median ≥1 mutation per Mb). Across cancer types and across breeds, the mutation rate is strongly associated with TP53 mutation, but not with PIK3CA mutation. The mutation rate is also associated with a mutation signature enriched in osteosarcoma of Golden Retrievers, independent of TP53 mutation. Finally, compared to other breeds examined, DNA repair genes appear to be less conserved in Golden Retriever which is predisposed to numerous cancers.

BackgroundAbout 20% of breast cancers in humans are basal-like, a subtype that is often triple negative and difficult to treat. An effective translational model for basal-like breast cancer (BLBC) is currently lacking and urgently needed. To determine if spontaneous mammary tumors in pet dogs could meet this need, we subtyped canine mammary tumors and evaluated the dog-human molecular homology at the subtype level.MethodsWe subtyped 236 canine mammary tumors from 3 studies by applying various subtyping strategies on their RNA-seq data. We then performed PAM50 classification with canine tumors alone, as well as with canine tumors combined with human breast tumors. We investigated differential gene expression, signature gene set enrichment, expression association, mutational landscape, and other features for dog-human subtype comparison.ResultsOur independent genome-wide subtyping consistently identified two molecularly distinct subtypes among the canine tumors. One subtype is mostly basal-like and clusters with human BLBC in cross-species PAM50 classification, while the other subtype does not cluster with any human breast cancer subtype. Furthermore, the canine basal-like subtype recaptures key molecular features (e.g., cell cycle gene upregulation, TP53 mutation) and gene expression patterns that characterize human BLBC. It is enriched histological subtypes that match human breast cancer, unlike the other canine subtype. However, about 33% of canine basal-like tumors are estrogen receptor negative (ER-) and progesterone receptor positive (PR+), which is rare in human breast cancer. Further analysis reveals that these ER-PR+ canine tumors harbor additional basal-like features, including upregulation of genes of interferon-γ response and of the Wnt-pluripotency pathway. Interestingly, we observed an association ofPGRexpression with gene silencing in all canine tumors, and with the expression of T cell exhaustion markers (e.g.,PDCD1) in ER-PR+ canine tumors.ConclusionsWe identify a canine mammary tumor subtype that molecularly resembles human BLBC overall, and thus could serve as a vital spontaneous animal model of this devastating breast cancer subtype. Our study also sheds light on the dog-human difference in the mammary tumor histology and the hormonal cycle.