Genomic landscapes of canine splenic angiosarcoma (hemangiosarcoma) contain extensive heterogeneity within and between patients

Abstract

Cancer genomic heterogeneity presents significant challenges for understanding oncogenic processes and for cancer’s clinical management. Variation in driver mutation frequency between patients with the same tumor type as well as within an individual patients’ cancer can shape the use of mutations as diagnostic, prognostic, and predictive biomarkers. We have characterized genomic heterogeneity between and within canine splenic hemangiosarcoma (HSA), a common naturally occurring cancer in pet dogs that is similar to human angiosarcoma (AS). HSA is a clinically, physiologically, and genomically complex canine cancer that may serve as a valuable model for understanding the origin and clinical impact of cancer heterogeneity. We conducted a prospective collection of 52 splenic masses from 43 dogs (27 HSA, 15 benign masses, and 1 stromal sarcoma) presenting for emergency care with hemoperitoneum secondary to a ruptured splenic mass. Multi-platform genomic analysis included matched tumor/normal targeted sequencing panel and exome sequencing. We found candidate somatic cancer driver mutations in 14/27 (52%) HSAs. Among recurrent candidate driver mutations, TP53 was most commonly mutated (30%) followed by PIK3CA (15%), AKT1 (11%), and CDKN2AIP (11%). We also identified significant intratumoral genomic heterogeneity, consistent with a branched evolution model, through multi-region exome sequencing of three distinct tumor regions from selected primary splenic tumors. These data provide new perspectives on the genomic landscape of this veterinary cancer and suggest a cross-species value for using HSA in pet dogs as a naturally occurring model of intratumoral heterogeneity.

New molecular targets in canine hemangiosarcoma—Comparative review and future of the precision medicine

“…Thus, precision medicine, which involves the utilization of genomic diagnostics to guide the clinical management, may be more of an impediment than an advantage in HSA cases. 36 Last but not least, HSA involves an increase in SULF1/2 expression with a concomitant increase in TGFβ cell signalling, which is associated with haemorrhages resulting from dysregulation of TGF β/VEGF cell signalling in this tumour. These compounds are also suspected to be involved in the growth, repair, and maintenance of vasculature.…”

“…121 It is highly probable that the results obtained in clinical trials in human patients can be used in veterinary medicine. 36 This assumption is based on identical amino acid (aa) sequences of mutated human and canine proteins, which actually correspond to well-known oncogenic mutations and are functionally relevant in activating downstream signalling. Moreover, the affected signalling pathway is an extremely conserved one during the phylogenetic development.…”

“…More likely small insertions/deletions and single nucleotide variants might be crucial for tumorigenesis 13 . Moreover, Wong et al 36 discovered that even in the same type of tumour located in various regions of the body both the histopathological structure of the tissue and molecular abnormalities (including driver mutations) differ significantly. Thus, precision medicine, which involves the utilization of genomic diagnostics to guide the clinical management, may be more of an impediment than an advantage in HSA cases 36 .…”

“…Moreover, Wong et al 36 discovered that even in the same type of tumour located in various regions of the body both the histopathological structure of the tissue and molecular abnormalities (including driver mutations) differ significantly. Thus, precision medicine, which involves the utilization of genomic diagnostics to guide the clinical management, may be more of an impediment than an advantage in HSA cases 36 . Last but not least, HSA involves an increase in SULF1/2 expression with a concomitant increase in TGFβ cell signalling, which is associated with haemorrhages resulting from dysregulation of TGF β/VEGF cell signalling in this tumour.…”

Genomic tumor analysis provides clinical guidance for the management of diagnostically challenging cancers in dogs

“…Once received, samples were grossly processed and embedded if not already performed (for formalin-fixed or fresh frozen tissues), tumor content was determined, and DNA was extracted as previously described within 2 to 3 days of receipt. Samples were then verified as having passed quality metrics and then underwent sequencing of targeted genomic regions enriched using a proprietary custom panel of hybridization-based capture probes to evaluate the presence of multiple mutation types, including single-nucleotide variants (SNVs), copy number variants (CNVs), and internal tandem duplications (ITDs) in the carefully selected 120 cancer genes (1,358 exonic regions and 429 exon-proximal regions of the genome across 11,554 probes targeting 482.3 kbp of sequence space) selected on the basis of our prior studies, 36,37 content of human cancer gene panels, and curation of canine and human cancer genomic biomarker literature (Appendix).…”