Abstract
BackgroundTransmissible cancers lie at the intersection of oncology and infectious disease, two traditionally divergent fields for which gene expression studies are particularly useful for identifying the molecular basis of phenotypic variation. In oncology, transcriptomics studies, which characterize the expression of thousands of genes, have identified processes leading to heterogeneity in cancer phenotypes and individual prognoses. More generally, transcriptomics studies of infectious diseases characterize interactions between host, pathogen, and environment to better predict population-level outcomes. Tasmanian devils have been impacted dramatically by a transmissible cancer (devil facial tumor disease; DFTD) that has led to widespread population declines. Despite initial predictions of extinction, populations have persisted at low levels, due in part to heterogeneity in host responses, particularly between sexes. However, the processes underlying this variation remain unknown.ResultsWe sequenced transcriptomes from healthy and DFTD-infected devils, as well as DFTD tumors, to characterize host responses to DFTD infection, identify differing host-tumor molecular interactions between sexes, and investigate the extent to which tumor gene expression varies among host populations. We found minimal variation in gene expression of devil lip tissues, either with respect to DFTD infection status or sex. However, 4088 genes were differentially expressed in tumors among our sampling localities. Pathways that were up- or downregulated in DFTD tumors relative to normal tissues exhibited the same patterns of expression with greater intensity in tumors from localities that experienced DFTD for longer. No mRNA sequence variants were associated with expression variation.ConclusionsExpression variation among localities may reflect morphological differences in tumors that alter ratios of normal-to-tumor cells within biopsies. Phenotypic variation in tumors may arise from environmental variation or differences in host immune response that were undetectable in lip biopsies, potentially reflecting variation in host-tumor coevolutionary relationships among sites that differ in the time since DFTD arrival.
Highlights
Transmissible cancers lie at the intersection of oncology and infectious disease, two traditionally divergent fields for which gene expression studies are useful for identifying the molecular basis of phenotypic variation
Samples were collected from wild devils between 2016 and 2018 from three distinct localities (Fig. 1): Black River (BR; first infected in 2016), Takone (TKN; first infected in 2011) and West Pencil
Volumes of sampled tumors did not significantly differ among localities We generated a total of 1,168,476,356 sequence reads, which were reduced to 1,167,199,873 following quality trimming and filtering
Summary
Transmissible cancers lie at the intersection of oncology and infectious disease, two traditionally divergent fields for which gene expression studies are useful for identifying the molecular basis of phenotypic variation. Transcriptomics studies, which characterize the expression of thousands of genes, have identified processes leading to heterogeneity in cancer phenotypes and individual prognoses. Transcriptomics studies of infectious diseases characterize interactions between host, pathogen, and environment to better predict population-level outcomes. Identification of the processes underlying cancer development as well as those associated with heterogeneity in its progression is critical for predicting both individual and population-level outcomes [1, 2]. Variation in gene expression among individuals can indicate how biotic and abiotic pressures underlie population-level responses. The fields of oncology and wildlife disease intersect in the case of transmissible cancers, which are clonal, transmissible tumors that are spread among individuals by the transfer of cancerous cells [15]
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