Franceschini Natasja, Verbruggen Bas, Tryfonidou Marianna A, Kruisselbrink Alwine B, Baelde Hans, de Visser Karin E, Szuhai Karoly, Cleton-Jansen Anne-Marie, Bovée Judith V M G
Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands.
Cancers (Basel). 2021 Mar 5;13(5):1126. doi: 10.3390/cancers13051126.
Sarcomas are rare mesenchymal tumors with a broad histological spectrum, but they can be divided into two groups based on molecular pathology: sarcomas with simple or complex genomics. Tumors with complex genomics can have aneuploidy and copy number gains and losses, which hampers the detection of early, initiating events in tumorigenesis. Often, no benign precursors are known, which is why good models are essential. The mesenchymal stem cell (MSC) is the presumed cell of origin of sarcoma. In this study, MSCs of murine and canine origin are used as a model to identify driver events for sarcomas with complex genomic alterations as they transform spontaneously after long-term culture. All transformed murine but not canine MSCs formed sarcomas after subcutaneous injection in mice. Using whole genome sequencing, spontaneously transformed murine and canine MSCs displayed a complex karyotype with aneuploidy, point mutations, structural variants, inter-chromosomal translocations, and copy number gains and losses. Cross-species analysis revealed that point mutations in are common in transformed murine and canine MSCs. Murine MSCs with a cre-recombinase induced deletion of exon 2-10 of transformed earlier compared to wild-type murine MSCs, confirming the contribution of loss of p53 to spontaneous transformation. Our comparative approach using transformed murine and canine MSCs points to a crucial role for p53 loss in the formation of sarcomas with complex genomics.
肉瘤是罕见的间充质肿瘤，具有广泛的组织学谱，但根据分子病理学可分为两组：基因组简单或复杂的肉瘤。基因组复杂的肿瘤可出现非整倍体以及拷贝数的增加和减少，这会妨碍对肿瘤发生早期起始事件的检测。通常，尚无已知的良性前体，这就是良好模型至关重要的原因。间充质干细胞（MSC）被认为是肉瘤的起源细胞。在本研究中，将源自小鼠和犬的MSC用作模型，以鉴定基因组改变复杂的肉瘤的驱动事件，因为它们在长期培养后会自发转化。所有转化的小鼠MSC（但不是犬MSC）在皮下注射到小鼠体内后都会形成肉瘤。通过全基因组测序，自发转化的小鼠和犬MSC显示出具有非整倍体、点突变、结构变异、染色体间易位以及拷贝数增加和减少的复杂核型。跨物种分析表明，[此处原文缺失具体基因名称]中的点突变在转化的小鼠和犬MSC中很常见。与野生型小鼠MSC相比，具有cre重组酶诱导的[此处原文缺失具体基因名称]外显子2 - 10缺失的小鼠MSC转化得更早，证实了p53缺失对自发转化的作用。我们使用转化的小鼠和犬MSC的比较方法表明p53缺失在基因组复杂的肉瘤形成中起关键作用。
