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 individual patients’ cancers can limit the power of mutations to serve as diagnostic, prognostic, and predictive biomarkers. We have characterized genomic heterogeneity between and within patients in 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 44 dogs (28 HSA, 15 benign masses, and 1 stromal sarcoma) presenting to emergency care with hemoperitoneum secondary to a ruptured splenic mass. Multi-platform genomic analysis included matched tumor/normal cancer gene panel and exome sequencing. We found candidate somatic cancer driver mutations in 14/28 (50%) HSAs. Among recurrent candidate driver mutations, TP53 was most commonly mutated (29%) followed by PIK3CA (14%), 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 perspective on the genomic landscape and comparative value of understanding HSA in pet dogs, particularly as a naturally occurring cancer bearing intratumoral heterogeneity.

Shared hotspot mutations in spontaneously arising cancers position dog as an unparalleled comparative model for precision therapeutics

“…Canine tumors provide a powerful platform for translational investigation 11,12,30 . Over the past decade, genomic characterization of canine cancers has highlighted the close biological and molecular similarities between several canine and human cancers, including lymphoma 14,15,31 , osteosarcoma 8,20,22 , hemangiosarcoma 17,23–25,27,32 , glioma 26 , melanoma 19 , mammary tumors 33–35 , and urothelial carcinoma 16,18 . Some of the somatic mutations identified in these canine cancers occur at the orthologous position to known mutational hotspots found in human cancers, including PIK3CA H1047 17,23 , BRAF V588 (also reported as V595; human BRAF V600) 16 , and FBXW7 R470 (human R465) 15 .…”

Identification of genomic alterations with clinical impact in canine splenic hemangiosarcoma

“…Common somatic mutations in this cohort - TP53 (41%, 30% - 93% previously reported), NRAS (18%, 0% - 24% previously reported), PIK3CA (17%, 15% - 60% previously reported), and PTEN (3%, 0% - 10% previously reported) were present at similar frequencies to previous reports. 8-12 However, mutations in both TP53 and PIK3CA were observed near the lower end of their reported frequency in the literature. Our finding that TP53 and PIK3CA are mutated more frequently in larger dogs may offer a potential explanation of the decreased prevalence of these mutations in our cohort, which included dogs as small as 4 kg.…”

“…Common somatic mutations in this cohort -TP53 (41%, 30% -93% previously reported), NRAS (18%, 0% -24% previously reported), PIK3CA (17%, 15% -60% previously reported), and PTEN (3%, 0% -10% previously reported) were present at similar frequencies to previous reports. [8][9][10][11][12] However, mutations in both TP53 and PIK3CA were observed near the lower end of their reported frequency in the literature.…”

“…[8][9][10][11][12] Loss-of-function mutations in the TP53 tumor-suppressor gene were most frequent across studies (29-93% of cases), as well as activating mutations of PIK3CA (14-60%) and NRAS (4-24%). [8][9][10][11][12] In one paper, increased PI3K pathway signaling was demonstrated in cases with either PIK3CA activating mutations or PTEN inactivating mutations, and increased MAPK/ERK pathway signaling was found in cases with NRAS activating mutations. 9 While both AS and HSA are genetically heterogeneous, there are some similarities, including mutations in TP53, PIK3CA (most common in primary breast AS 13 ), PTEN, and NRAS 14,15 , and MAPK/ERK and PI3K pathway activation.…”

“…Previous studies have performed whole exome sequencing (WES) and targeted next-generation sequencing (NGS) of canine HSA tumors, finding potential driver mutations in TP53, PIK3CA, NRAS, and PTEN, among other genes. [8][9][10][11][12] Loss-of-function mutations in the TP53 tumor-suppressor gene were most frequent across studies (29-93% of cases), as well as activating mutations of PIK3CA (14-60%) and NRAS (4-24%). [8][9][10][11][12] In one paper, increased PI3K pathway signaling was demonstrated in cases with either PIK3CA activating mutations or PTEN inactivating mutations, and increased MAPK/ERK pathway signaling was found in cases with NRAS activating mutations.…”