Shing Danielle C, McMullan Dominic J, Roberts Paul, Smith Kim, Chin Suet-Feung, Nicholson James, Tillman Roger M, Ramani Pramila, Cullinane Catherine, Coleman Nicholas
Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 2XZ, UK.
Cancer Res. 2003 Aug 1;63(15):4568-76.
Ewing's tumors are rare pediatric neoplasms that are characterized by specific chromosomal translocations and gene rearrangements. All of the fusion genes reported to date in Ewing's tumors juxtapose the EWS gene at 22q12 to an ETS-related gene, the most common of which are FLI1 at 11q24 and ERG at 21q22. We present here four cases of Ewing's tumor, which showed no evidence of a EWS gene rearrangement, but instead contained translocations involving 16p11 and 21q22. A rearrangement involving the same chromosome bands, t(16;21)(p11;q22), is found in rare cases of acute myeloid leukemia and fuses the FUS gene at 16p11 to the ERG gene at 21q22. In two of our Ewing's tumor cases, we were able to show at the sequence level that the translocation between chromosomes 16 and 21 similarly results in a FUS/ERG fusion. In one case, exons 1-5 and most of exon 6 of FUS were fused in-frame to exon 9 of ERG; in the other case, FUS exons 1-7 were fused in-frame to ERG exons 8-9. The functional fusion transcript is expected to be expressed from the der(21)t(16;21) derivative. In the two other t(16;21)-positive Ewing's cases, we performed bacterial artificial chromosome fluorescence in situ hybridization analysis on metaphases and interphase nuclei to demonstrate colocalization of bacterial artificial chromosomes containing FUS and ERG genes, also highly suggestive of fusion gene formation. These represent the first four cases where FUS, rather than EWS, is rearranged with an ETS-family transcription factor in Ewing's tumors. Our data provide additional evidence that the transactivation domains of the TET family of RNA-binding proteins (such as EWS and FUS) are interchangeable, and suggests a novel mechanism of oncogenesis in Ewing's tumors.
尤因肉瘤是一种罕见的儿童肿瘤，其特征为特定的染色体易位和基因重排。迄今为止，在尤因肉瘤中报道的所有融合基因都将位于22q12的EWS基因与一个ETS相关基因并列，其中最常见的是位于11q24的FLI1和位于21q22的ERG。我们在此展示四例尤因肉瘤病例，这些病例未显示EWS基因重排的证据，而是包含涉及16p11和21q22的易位。在罕见的急性髓系白血病病例中发现了涉及相同染色体带t(16;21)(p11;q22)的重排，该重排将位于16p11的FUS基因与位于21q22的ERG基因融合。在我们的两例尤因肉瘤病例中，我们能够在序列水平上表明16号和21号染色体之间的易位同样导致了FUS/ERG融合。在一例中，FUS的外显子1 - 5和大部分外显子6与ERG的外显子9框内融合；在另一例中，FUS外显子1 - 7与ERG外显子8 - 9框内融合。预计功能性融合转录本将从der(21)t(16;21)衍生染色体上表达。在另外两例t(16;21)阳性的尤因肉瘤病例中，我们对中期和间期细胞核进行了细菌人工染色体荧光原位杂交分析，以证明包含FUS和ERG基因的细菌人工染色体的共定位，这也高度提示融合基因的形成。这些是尤因肉瘤中首例FUS而非EWS与ETS家族转录因子重排的四例病例。我们的数据提供了额外的证据，表明RNA结合蛋白TET家族（如EWS和FUS）的反式激活结构域是可互换的，并提示了尤因肉瘤中新的肿瘤发生机制。
