PO.IM02.06 · 免疫学
通过人类血管肉瘤与犬血管肉瘤的比较基因组分析揭示驱动突变和致癌通路改变的保守性
Conservation of driver mutations and oncogenic pathway alterations revealed through a comparative genomic analysis of human angiosarcoma and canine hemangiosarcoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
血管肉瘤（AS）是一种罕见且侵袭性强的内皮源性恶性肿瘤，占人类软组织肉瘤的 <2%。其低发病率、基因组异质性以及具有代表性的临床前模型稀缺，阻碍了有效治疗手段的开发进展。对两个 cBioPortal 队列（n=131）的整合基因组分析鉴定出 TP53（26%）、KDR（17.6%）、POT1（17.6%）、PIK3CA（14.5%）、FLT4（11.5%）、PTPRB（11.5%）和 NRAS（5.3%）的反复改变，凸显了 DNA 损伤反应、PI3K/AKT/mTOR 和血管生成受体信号的普遍破坏。然而，AS 的罕见性限制了功能验证和生物标志物驱动的治疗开发。犬血管肉瘤（HSA）是一种生物学上类似的血管肿瘤，自发发生且发病率高得多，为在免疫健全宿主中建立 AS 模型提供了独特机会。对来自 FidoCure 精准医学平台的 HSA 进行的大规模分析（n=1,177）揭示了重叠的突变，包括 TP53（54.9%）、PIK3CA（29.9%）、NRAS（15.3%）、FLT4（3.6%）、PTEN（3.4%）和 KDR（2.6%），与人类图谱相吻合。跨物种分析显示出显著的分子平行性。两个物种中的 PIK3CA 突变均聚集于螺旋结构域和激酶结构域，与通路激活一致。虽然在经典热点（H1047R/L/Y）的突变在 HSA 中占主导，但 AS 被发现携带异质性变异（P124L、T957P、M1043V/I）。TP53 变异定位于保守的 DNA 结合区域（人类 R175、R248、R273；犬 R164H、C228R/Y、R263H、R272H），提示肿瘤抑制功能的趋同性丧失。KDR、NRAS 和 PTEN 的改变同样跨物种破坏了 VEGFR2、RAS/MAPK 和 PI3K 信号通路。总体而言，这些发现揭示了血管肉瘤发生中分子驱动因素的深度进化保守性。犬 HSA 忠实地重现了人类 AS 的遗传复杂性和治疗易感性，为免疫健全背景下的生物标志物发现、靶向治疗验证和转化肿瘤学研究建立了稳健的比较平台。
查看英文原文 English abstract
Angiosarcoma (AS) is a rare and aggressive endothelial malignancy, representing <2% of soft tissue sarcomas in humans. Progress in developing effective therapies has been hindered by its low incidence, genomic heterogeneity, and the scarcity of representative preclinical models.Integrative genomic analyses of two cBioPortal cohorts (n=131) identified recurrent alterations in TP53 (26%), KDR (17.6%), POT1 (17.6%), PIK3CA (14.5%), FLT4 (11.5%), PTPRB (11.5%), and NRAS (5.3%), highlighting pervasive disruptions of DNA damage response, PI3K/AKT/mTOR, and angiogenic receptor signaling. However, the rarity of AS limits functional validation and biomarker-driven therapy development.Canine hemangiosarcoma (HSA) is a biologically analogous vascular tumor that occurs spontaneously with far higher incidence, offering a unique opportunity to model AS in an immunocompetent host. Large-scale profiling of HSA from the FidoCure Precision Medicine Platform (n=1,177) revealed overlapping mutations in TP53 (54.9%), PIK3CA (29.9%), NRAS (15.3%), FLT4 (3.6%), PTEN (3.4%), and KDR (2.6%), mirroring the human landscape.Cross-species analyses showed striking molecular parallels. PIK3CA mutations in both species clustered in the helical and kinase domains, consistent with pathway activation. While mutation at the canonical hotspot (H1047R/L/Y) predominated in HSA, AS was found to harbor heterogeneous variants (P124L, T957P, M1043V/I). TP53 variants localized to conserved DNA-binding regions (human R175, R248, R273; canine R164H, C228R/Y, R263H, R272H), indicating convergent loss of tumor-suppressor function. KDR, NRAS, and PTEN alterations similarly disrupted VEGFR2, RAS/MAPK, and PI3K signaling pathways across species.Collectively, these findings reveal deep evolutionary conservation of molecular drivers in vascular sarcomagenesis. Canine HSA faithfully recapitulates the genetic complexity and therapeutic vulnerabilities of human AS, establishing a robust comparative platform for biomarker discovery, targeted therapy validation, and translational oncology research within an immunocompetent context.
利益披露 Disclosure
L. Rodrigues, None..
G. Harvey, None..
G. Post, None..
B. Lewis, None..
A. Hull, None..
A. O'Grady, None..
L. Lambert, None..
C. Lopes, None..
T. Allen, None.