Immune pathways and TP53 missense mutations are associated with longer survival in canine osteosarcoma

Abstract

Osteosarcoma affects about 2.8% of dogs with cancer, with a one-year survival rate of approximately 45%. The purpose of this study was to characterize mutation and expression profiles of osteosarcoma and its association with outcome in dogs. The number of somatic variants identified across 26 samples ranged from 145 to 2,697 with top recurrent mutations observed in TP53 and SETD2. Additionally, 47 cancer genes were identified with copy number variations. Missense TP53 mutation status and low pre-treatment blood monocyte counts were associated with a longer disease-free interval (DFI). Patients with longer DFI also showed increased transcript levels of anti-tumor immune response genes. Although, T-cell and myeloid cell quantifications were not significantly associated with outcome; immune related genes, PDL-1 and CD160, were correlated with T-cell abundance. Overall, the association of gene expression and mutation profiles to outcome provides insights into pathogenesis and therapeutic interventions in osteosarcoma patients.

The genomic landscape of canine osteosarcoma cell lines reveals conserved structural complexity and pathway alterations

“…The highest contributions were made by signatures SBS1, SBS40, and SBS5 (Fig 2B , S4 Fig). Signatures SBS1, SBS5, SBS8, SBS17a, SBS17b, SBS30, and SBS40 have previously been reported in human OS samples [50], while signatures SBS1, SBS8, SBS9, and SBS17b have been reported in canine OS [16][17][18][19].…”

“…We identified five published WES or WGS datasets of canine OS tissue (Sakthikumar, et al [16], Gardner, et al [18], Das, et al [17], Chu, et al [19]) or cell lines (Das, et al [1]). Variant…”

“…We compared our simple somatic mutation calls to those previously reported in WES/ WGS canine OS tissue samples (S6 Table) [16][17][18][19]. Of the 3836 genes with SNVs/INDELs reported in at least one OS tumor in these studies, 272 (7%) were also mutated in at least one cell line.…”

“…For example, a variety of established canine osteosarcoma (OS) cell lines are employed in preclinical studies; however, they have been primarily characterized using methods that define a relatively narrow spectrum of molecular and pathway alterations. A limited number of OS lines have been evaluated using RNA-seq and WES, demonstrating conserved transcriptional signatures and point mutations in TP53 with sequenced tumors [1,[15][16][17]. We and others have recently characterized canine primary OS using WGS, WES and RNA-sequencing, demonstrating significant structural complexity, including aberrations in SETD2, DMD, DLG2 and MYC, among others [16][17][18][19].…”

“…A limited number of OS lines have been evaluated using RNA-seq and WES, demonstrating conserved transcriptional signatures and point mutations in TP53 with sequenced tumors [1,[15][16][17]. We and others have recently characterized canine primary OS using WGS, WES and RNA-sequencing, demonstrating significant structural complexity, including aberrations in SETD2, DMD, DLG2 and MYC, among others [16][17][18][19]. Several of these were not noted in the prior interrogation of canine OS cell lines, largely due to the fact that a defining feature of canine OS is the presence of large structural changes that are more difficult to detect via WES [18][19][20].…”