Comparative whole transcriptome analysis of gene expression in three canine soft tissue sarcoma types

Abstract

Soft tissue sarcomas are pleiotropic tumors of mesenchymal cell origin. These tumors are rare in humans but common in veterinary practice, where they comprise up to 15% of canine skin and subcutaneous cancers. Because they present similar morphologies, primary sites, and growth characteristics, they are treated similarly, generally by surgical resection followed by radiation therapy. Previous studies have examined a variety of genetic changes as potential drivers of tumorigenesis and progression in soft tissue sarcomas as well as their use as markers for soft tissue sarcoma subtypes. However, few studies employing next generation sequencing approaches have been published. Here, we have examined gene expression patterns in canine soft tissue sarcomas using RNA-seq analysis of samples obtained from archived formalin-fixed and paraffin-embedded tumors. We provide a computational framework for using resulting data to categorize tumors, perform cross species comparisons and identify genetic changes associated with tumorigenesis. Functional overrepresentation analysis of differentially expressed genes further implicate both common and tumor-type specific transcription factors as potential mediators of tumorigenesis and aggression. Implications for tumor-type specific therapies are discussed. Our results illustrate the potential utility of this approach for the discovery of new therapeutic approaches to the management of canine soft tissue sarcomas and support the view that both common and tumor-type specific mechanisms drive the development of these tumors.

Integrated analysis of canine soft tissue sarcomas identifies recurrent mutations inTP53, KMTgenes andPDGFBfusions

“…This could be due to variability in analyses techniques and/or histological characterization of canine PNSTs. Similar to our study, a recent RNAseq study of canine STS subtypes, also showed elevated expression of GLI and CLECB1 in PNST samples (48)…”

“…This could be due to variability in analyses techniques and/or histological characterization of canine PNSTs. Similar to our study, a recent RNAseq study of canine STS subtypes, also showed elevated expression of GLI and CLECB1 in PNST samples (48), but failed to confirm elevation of S100 and vimentin in PNST samples. Further studies at both transcript and protein levels are required to determine specific molecular markers for PNST.…”

Efficacy and toxicity of carboplatin in the treatment of macroscopic mesenchymal neoplasia in dogs

“…However, responses remained short lived, ranging from 7 to 90 days. This is similar to previous findings evaluating HSA and STS responses to other chemotherapy agents 18,19,22,38–41,51 ; where despite sharing a mesenchymal origin, these tumours demonstrate diverging genomic landscapes and clinical behaviours 53,54 . The gene expression profiles and mutations of HSA and STS may impact differences in chemosensitivity 53–57 .…”

“…This is similar to previous findings evaluating HSA and STS responses to other chemotherapy agents 18,19,22,[38][39][40][41]51 ; where despite sharing a mesenchymal origin, these tumours demonstrate diverging genomic landscapes and clinical behaviours. 53,54 The gene expression profiles and mutations of HSA and STS may impact differences in chemosensitivity. [53][54][55][56][57] Furthermore, HSA display rapid progression resulting from high mitotic activity, 58,59 making them potentially susceptible to cytotoxic chemotherapy.…”

“…53,54 The gene expression profiles and mutations of HSA and STS may impact differences in chemosensitivity. [53][54][55][56][57] Furthermore, HSA display rapid progression resulting from high mitotic activity, 58,59 making them potentially susceptible to cytotoxic chemotherapy. These factors could explain the difference in response observed between canine STS and HSA patients.…”