Comparative Genomics Reveals Shared Mutational Landscape in Canine Hemangiosarcoma and Human Angiosarcoma
Comparative Genomics Reveals Shared Mutational Landscape in Canine Hemangiosarcoma and Human Angiosarcoma
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DOI：
10.1158/1541-7786.mcr-19-0221
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发表时间：
2019-12-01
影响因子：
5.2
通讯作者：
Lindblad-Toh, Kerstin
中科院分区：
文献类型：
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作者：
Megquier, Kate;Turner-Maier, Jason;Lindblad-Toh, Kerstin
血管肉瘤是一种高度侵袭性的血管形成细胞癌，几乎没有有效的治疗选择，患者死亡率很高。它既罕见，又具有异质性，使得大规模、强大的基因组研究几乎是不可能的。狗通常患有一种类似的癌症，称为血管肉瘤，像金毛猎犬这样的品种携带着使它们处于高风险的遗传因素。如果犬血管肉瘤和人类血管肉瘤的临床相似性反映了共同的基因组病因学，狗可能是推进血管肉瘤研究的迫切需要的模型。我们通过全外显子组测序(47个金毛猎犬血管肉瘤)和RNA测序(来自多个品种的74个血管肉瘤)评估了犬血管肉瘤的基因组图景。体细胞编码突变最常见的是抑癌基因TP53(59.6%)以及PI3K途径中的两个基因：癌基因PIK3CA(29.8%)及其调节亚基PIK3R1(8.5%)。主要的突变特征是与年龄相关的胞嘧啶脱氨基为胸腺嘧啶。据报道，在人类血管肉瘤中，CDKN2A/B被反复删除，VEGFA、KDR和KIT反复获得。我们将狗的数据与血管肉瘤项目最近发布的人类数据进行了比较，发现许多相同的基因和途径显著丰富了体细胞突变，特别是在乳房和内脏血管肉瘤中。犬血管肉瘤与人类乳腺和内脏血管肉瘤的基因组图谱非常接近，是研究这种毁灭性疾病发病机制的有力工具。
Angiosarcoma is a highly aggressive cancer of blood vessel-forming cells with few effective treatment options and high patient mortality. It is both rare and heterogenous, making large, well-powered genomic studies nearly impossible. Dogs commonly suffer from a similar cancer, called hemangiosarcoma, with breeds like the golden retriever carrying heritable genetic factors that put them at high risk. If the clinical similarity of canine hemangiosarcoma and human angiosarcoma reflects shared genomic etiology, dogs could be a critically needed model for advancing angiosarcoma research. We assessed the genomic landscape of canine hemangiosarcoma via whole-exome sequencing (47 golden retriever hemangiosarcomas) and RNA sequencing (74 hemangiosarcomas from multiple breeds). Somatic coding mutations occurred most frequently in the tumor suppressor TP53 (59.6% of cases) as well as two genes in the PI3K pathway: the oncogene PIK3CA (29.8%) and its regulatory subunit PIK3R1 (8.5%). The predominant mutational signature was the age-associated deamination of cytosine to thymine. As reported in human angiosarcoma, CDKN2A/B was recurrently deleted and VEGFA, KDR, and KIT recurrently gained. We compared the canine data to human data recently released by The Angiosarcoma Project, and found many of the same genes and pathways significantly enriched for somatic mutations, particularly in breast and visceral angiosarcomas. Canine hemangiosarcoma closely models the genomic landscape of human angiosarcoma of the breast and viscera, and is a powerful tool for investigating the pathogenesis of this devastating disease.