Analysis of transcriptional drivers in canine pulmonary adenocarcinoma
Primary canine pulmonary adenocarcinomas (cPACs) and human never-smoker lung cancer (hNSLC) share underlying pathological and genetic features. In cPAC, we have previously identified frequent mutations in the HER2 gene, which is a member of the broader epidermal growth factor receptor (EGFR) pathway. This pathway is commonly activated in hNSLC directly through EGFR mutation. In order to comprehensively evaluate diverse routes to EGFR pathway activation in cPAC, we performed multiplatform genomic analysis on a cohort of cPACs via whole genome, whole exome, and amplicon sequencing. We then evaluated gene expression patterns from RNAseq and performed hierarchical clustering of COSMIC and EGFR pathway genes to look for associations with HER2 mutation status across the cohort. We also detected novel fusions and confirmed a previously identified fusion relevant to EGFR activation, which we confirmed in whole genome and RNA sequencing data. However, the unsupervised hierarchical clustering of the gene expression patterns shows little correlation between HER2 mutation and fusion status, suggesting that the sources and transcriptional effects of EGFR pathway activation in cPAC are complex. From the fusion calling, we confirmed the presence of a fusion found in 3 samples. This particular fusion has also been implicated in human pulmonary adenocarcinoma, and the hierarchical clustering also shows that these 3 samples containing this fusion cluster together and thus have close correlation in gene expression. The presence of this fusion in cPACs suggests a potential alternate route of activation of the EGFR pathway, setting the stage for further research into the pathological impacts of this fusion.