1] Department of Orthopedics, Section III, Clinical Sciences, Lund University, 22185 Lund, Sweden [2] Department of Oncology, Section V, Clinical Sciences, Lund University, 22185 Lund, Sweden.
Division of Surgical Oncology, Department of Surgery, University Medical Center Groningen, University of Groningen, Hanzeplein 1, PO Box 30.001, 9700 Groningen, The Netherlands.
Br J Cancer. 2014 Jul 15;111(2):407-12. doi: 10.1038/bjc.2014.359. Epub 2014 Jul 1.
Angiosarcomas may develop as primary tumours of unknown cause or as secondary tumours, most commonly following radiotherapy to the involved field. The different causative agents may be linked to alternate tumorigenesis, which led us to investigate the genetic profiles of morphologically indistinguishable primary and secondary angiosarcomas.
Whole-genome (18k) c-DNA-mediated annealing, selection, extension and ligation analysis was used to genetically profile 26 primary and 29 secondary angiosarcomas. Key findings were thereafter validated using RT-qPCR, immunohistochemistry and validation of the gene signature to an external data set.
In total, 103 genes were significantly deregulated between primary and secondary angiosarcomas. Secondary angiosarcomas showed upregulation of MYC, KIT and RET and downregulation of CDKN2C. Functional annotation analysis identified multiple target genes in the receptor protein tyrosine kinase pathway. The results were validated using RT-qPCR and immunohistochemistry. Further, the gene signature was applied to an external data set and, herein, distinguished primary from secondary angiosarcomas.
Upregulation of MYC, KIT and RET and downregulation of CDKN2C characterise secondary angiosarcoma, which implies possibilities for diagnostic application and a mechanistic basis for therapeutic evaluation of RET-kinase-inhibitors in these highly aggressive tumours.
血管肉瘤可作为原因不明的原发性肿瘤发生，也可作为继发性肿瘤发生，最常见于受累野放疗后。不同的致病因子可能与不同的肿瘤发生相关，这促使我们研究形态上无法区分的原发性和继发性血管肉瘤的遗传特征。
采用全基因组（18k）cDNA 介导的退火、选择、延伸和连接分析技术，对 26 例原发性和 29 例继发性血管肉瘤进行基因谱分析。随后，使用 RT-qPCR、免疫组织化学和基因特征验证对外部数据集进行验证。
原发性和继发性血管肉瘤之间共有 103 个基因显著失调。继发性血管肉瘤中 MYC、KIT 和 RET 上调，CDKN2C 下调。功能注释分析确定了受体酪氨酸激酶通路中的多个靶基因。结果使用 RT-qPCR 和免疫组织化学进行了验证。此外，该基因特征被应用于外部数据集，并在此区分了原发性和继发性血管肉瘤。
MYC、KIT 和 RET 的上调以及 CDKN2C 的下调特征是继发性血管肉瘤的特征，这意味着在这些高度侵袭性肿瘤中，诊断应用和 RET-激酶抑制剂治疗评估的机制基础具有可能性。
