Chordomas are rare, slow-growing neoplasms thought to arise from the foetal notochord remnant. A limited number of studies that examined the mutational profiles in chordomas identified potential driver mutations, including duplication in the TBXT gene (encoding brachyury), mutations in the PI3K/AKT signaling pathway, and loss of the CDKN2A gene. Most chordomas remain without clear driver mutations, and no fusion genes have been identified thus far. We discovered a novel TERT in-frame fusion involving RPH3AL (exon 5) and TERT (exon 2) in the index chordoma case. We screened a discovery cohort of 18 additional chordoma cases for TERT gene rearrangement by FISH, in which TERT rearrangement was identified in one additional case. In our independent, validation cohort of 36 chordomas, no TERT rearrangement was observed by FISH. Immunohistochemistry optimized for nuclear TERT expression showed at least focal TERT expression in 40/55 (72.7%) chordomas. Selected cases underwent molecular genetic profiling, which showed low tumor mutational burdens (TMBs) without obvious driver oncogenic mutations. We next examined a cohort of 1,913 solid tumor patients for TERT rearrangements, and TERT fusions involving exon 2 were observed in 7/1,913 (0.4%) cases. The seven tumors comprised five glial tumors, and two poorly differentiated carcinomas. In contrast to chordomas, the other TERT-rearranged tumors were notable for higher TMBs, frequent TP53 mutations (6/7) and presence of other driver oncogenic mutations, including a concurrent fusion (TRIM24-MET). In conclusion, TERT gene rearrangements are seen in a small subset (2/55, 3.6%) of chordomas. In contrast to other TERT-rearranged tumors, where the TERT rearrangements are likely passenger events, the possibility that TERT protein overexpression representing a key event in chordoma tumorigenesis is left open.

脊索瘤是罕见的、生长缓慢的肿瘤，被认为是由胎儿脊索残余物引起的。检查脊索瘤突变谱的少数研究确定了潜在的驱动突变，包括TBXT基因（编码 brachyury）的重复、PI3K/AKT 信号通路的突变和CDKN2A基因的缺失。大多数脊索瘤仍然没有明确的驱动突变，迄今为止还没有发现融合基因。我们在索引脊索瘤病例中发现了一种涉及RPH3AL（外显子 5）和TERT（外显子 2）的新型TERT帧内融合。我们通过 FISH筛选了 18 个额外脊索瘤病例的发现队列以进行TERT基因重排，其中在另外一个病例中发现了TERT重排。在我们的 36 个脊索瘤的独立验证队列中，FISH 未观察到TERT重排。针对核 TERT 表达优化的免疫组织化学显示，40/55 (72.7%) 脊索瘤中至少有局灶性 TERT 表达。选定的病例进行了分子遗传分析，结果显示低肿瘤突变负荷 (TMB)，没有明显的驱动致癌突变。我们接下来检查了 1,913 名实体瘤患者的TERT重排队列，在 7/1,913 (0.4%) 例中观察到涉及外显子 2 的TERT融合。七个肿瘤包括五个神经胶质瘤和两个低分化癌。与脊索瘤相比，另一个TERT重排肿瘤以更高的 TMB、频繁的TP53突变 (6/7) 和其他驱动致癌突变的存在而著称，包括并发融合 ( TRIM24-MET )。总之，在脊索瘤的一小部分 (2/55, 3.6%) 中可以看到TERT基因重排。与其他TERT重排肿瘤相比，其中TERT重排可能是乘客事件，代表脊索瘤肿瘤发生中关键事件的 TERT 蛋白过表达的可能性是开放的。