Department of Human Genetics, Medical University of Graz, Graz, Austria.
Institute of Pathology, Medical University of Graz, Graz, Austria.
Mod Pathol. 2017 Dec;30(12):1698-1709. doi: 10.1038/modpathol.2017.94. Epub 2017 Aug 4.
Myxofibrosarcomas are morphologically heterogeneous soft tissue sarcomas lacking a specific immunohistochemical expression profile and recurrent genetic changes. The study was designed to gain further insights into the molecular landscape of myxofibrosarcomas by targeted re-sequencing of known cancer driver hotspot mutations and the analysis of genomewide somatic copy number alterations. A well-defined group of myxofibrosarcomas, including myxofibrosarcomas G1 (n=6), myxofibrosarcomas G3 (n=7), myxofibrosarcomas with morphologically heterogeneous and independently selectable G1 and G3 areas within a tumor (n=8), and myxofibrosarcomas G3 with subsequent tumor recurrence (n=1) or metastatic disease (n=3) were evaluated. Mutational analysis demonstrated mutations in TP53, PTEN, FGFR3, CDKN2A, and RB1. TP53 mutations were seen in 11 (44%) of patients and detected in myxofibrosarcomas G1, G3, with heterogeneous morphology and G3 with subsequent metastases in 1 patient (16%), 3 patients (42%), 2 patients (62.5%), and 3 patients (75%), respectively. Additional mutations were detected in 2 patients, intratumoral mutational heterogeneity in 1 patient. We observed a variety of copy number alterations typical for myxofibrosarcomas, with higher numbers in G3 compared with G1 myxofibrosarcomas. Cluster analysis revealed distinctive features especially in metastatic and recurrent disease. Focal alterations affected CDKN2A, CCND1, CCNE1, EGFR, EPHA3, EPHB1, FGFR1, JUN, NF1, RB1, RET, TP53, and additional novel amplifications in CCNE1, KIT, EGFR, RET, BRAF, NTRK2 were seen in G3 compared with the G1 tumor areas. The total number of focal events in G1 versus G3 tumors differed significantly (P=0.0014). TRIO and RICTOR co-amplification was seen in 8 (44%) G3 and 1 (10%) G1 myxofibrosarcomas and RICTOR amplification alone in 4 (40%) G1 myxofibrosarcomas. TRIO amplification was significantly (P=0.0218) higher in G3 myxofibrosarcomas indicating a late genetic event. These findings support the use of expanded molecular profiling in myxofibrosarcomas to detect drug-able targets to allow patients to participate in basket trials.
黏液纤维肉瘤是形态学上具有异质性的软组织肉瘤，缺乏特定的免疫组织化学表达谱和反复发生的遗传改变。本研究旨在通过靶向重测序已知的癌症驱动热点突变和分析全基因组体细胞拷贝数改变，进一步深入了解黏液纤维肉瘤的分子特征。我们对一组明确的黏液纤维肉瘤进行了评估，包括 G1 型黏液纤维肉瘤（n=6）、G3 型黏液纤维肉瘤（n=7）、肿瘤内具有形态学异质性且可独立选择 G1 和 G3 区域的黏液纤维肉瘤（n=8）以及具有随后肿瘤复发（n=1）或转移疾病（n=3）的 G3 型黏液纤维肉瘤。突变分析显示 TP53、PTEN、FGFR3、CDKN2A 和 RB1 发生突变。11 例（44%）患者存在 TP53 突变，在 G1 型、G3 型黏液纤维肉瘤、形态学具有异质性的黏液纤维肉瘤和随后发生转移的 G3 型黏液纤维肉瘤中分别有 1 例（16%）、3 例（42%）、2 例（62.5%）和 3 例（75%）患者中检测到该突变。另外 2 例患者检测到其他突变，1 例患者存在肿瘤内突变异质性。我们观察到各种典型的黏液纤维肉瘤拷贝数改变，G3 型黏液纤维肉瘤的拷贝数改变高于 G1 型黏液纤维肉瘤。聚类分析显示，特别是在转移性和复发性疾病中存在独特的特征。局灶性改变影响 CDKN2A、CCND1、CCNE1、EGFR、EPHA3、EPHB1、FGFR1、JUN、NF1、RB1、RET、TP53，以及在 G3 型黏液纤维肉瘤中观察到的 CCNE1、KIT、EGFR、RET、BRAF、NTRK2 中的额外新型扩增。G1 型与 G3 型肿瘤之间的局灶性事件总数差异显著（P=0.0014）。在 8 例（44%）G3 型和 1 例（10%）G1 型黏液纤维肉瘤中观察到 TRIO 和 RICTOR 共扩增，在 4 例（40%）G1 型黏液纤维肉瘤中仅观察到 RICTOR 扩增。G3 型黏液纤维肉瘤中 TRIO 扩增显著更高（P=0.0218），表明这是一个晚期遗传事件。这些发现支持在黏液纤维肉瘤中使用扩展的分子谱分析来检测可靶向药物的靶点，以允许患者参与篮子试验。
