Comparison of the oncogenomic landscape of canine and feline hemangiosarcoma shows novel parallels with human angiosarcoma

Abstract

Angiosarcoma (AS) is a highly aggressive tumor of blood and lymphatic vessels in humans that carries a poor prognosis. The rarity of AS, together with its heterogeneous nature, and locations (skin, breast, visceral organs and deep soft tissues), makes understanding the pathogenesis of AS challenging. Dogs and cats spontaneously develop hemangiosarcoma (HSA), an aggressive tumor that shares many histopathological and clinical similarities to AS. To investigate the genetic suitability of spontaneously occurring HSA as a model for AS, we sequenced ∼1,000 cancer genes in 41 cases of HSA and matched germline tissue; 15 canine visceral HSAs, 13 canine skin HSAs and 13 feline skin HSAs. Analysis of visceral HSAs from dogs presenting with concurrent splenic and cardiac neoplasms showed that the tumors were not independent primaries, consistent with the highly metastatic nature of HSA. Comparison of canine and feline HSA to human AS revealed that several driver genes were recurrently mutated in both species, such as TP53, PIK3CA, ATRX, GRIN2A and LRP1B. In the germlines, by focusing specifically on canine and feline orthologs of human AS risk genes, we identified several candidate pathogenic variants. Similar to AS, a UV mutational signature was found in a subset of canine cutaneous HSAs. Furthermore, both AS and canine HSA show differing mutational profiles between tissue sites. Our characterization of canine and feline HSA demonstrate many important parallels to AS and provides hope that future studies on these cancers will benefit patients of all three species.

Genetic context of oncogenic drivers dictates vascular sarcoma development in aP2‐Cre mice

“…Such studies have identified recurrent putative driver mutations in genes such as TP53, KDR, PIK3CA, RAS, ARID1A, POT1, PTPRB, and PLCG1. Similar mutations have been reported recently in studies of canine hemangiosarcomas where TP53, PIK3CA, NRAS, PTEN, and PLCG1 are the most commonly mutated genes [11][12][13][14]. These studies have begun to reveal common aberrations among specific anatomic locations and subtypes of tumors.…”

The immunohistochemical detection of peroxiredoxin 1 and 2 in canine spontaneous vascular endothelial tumors

“…Human AS accounts for only 1% of all human malignant tumors, making research difficult. However, canine HSA occurs 5-20 times more frequently than human AS, accounting for approximately 7% of canine malignancies [17,40]. The histopathological features of canine HSA are similar to those of human AS [40].…”

“…However, canine HSA occurs 5-20 times more frequently than human AS, accounting for approximately 7% of canine malignancies [17,40]. The histopathological features of canine HSA are similar to those of human AS [40]. Furthermore, both human AS and canine HSA exhibit certain mutations in several genes, such as TP53, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α, and lowdensity lipoprotein receptor-related protein 1 B [11,28].…”

Feline Oncogenomics: What Do We Know about the Genetics of Cancer in Domestic Cats?

“…There is only one study that has looked at the genetics of HSA in cats. A targeted sequencing approach was taken to look at ~1000 cancer-associated genes in paired tumour-normal samples of 13 feline cutaneous HSA cases [ 120 ]. The most recurrently mutated genes in the HSA samples were TP53 (6/13, 46% cases) and NOTCH1 (2/13, 15% cases) [ 120 ].…”

“…A targeted sequencing approach was taken to look at ~1000 cancer-associated genes in paired tumour-normal samples of 13 feline cutaneous HSA cases [ 120 ]. The most recurrently mutated genes in the HSA samples were TP53 (6/13, 46% cases) and NOTCH1 (2/13, 15% cases) [ 120 ]. It is interesting to note that in human HFNS AS, the most commonly mutated gene is TP53 (9/19 patients, 47% cases), with NOTCH1 also being frequently mutated (5/19 samples, 26% cases) [ 120 ].…”