Frequent fusion of JAZF1 and JJAZ1 genes in endometrial stromal tumors

Endometrial stromal tumors represent a spectrum of neoplasms with uncertain biological relationships and they range from benign proliferations to aggressive malignancies. Controversies in the classification and relationship of the tumors can result in diagnostic difficulties; however, a molecular marker, a recurrent balanced translocation, has recently been described in low grade endometrial stromal sarcomas (LG-ESS). Our work identified the genes involved in the t(7;17)(p15;q21).; Characterization of the chromosome 7 breakpoint by fluorescence in situ hybridization identified a YAC clone that was disrupted by the translocation. By isolating BAC clones in the breakpoint region, preliminary sequence data for much of this region was found and a novel gene encoding a zinc finger protein was identified. A probe containing the third exon of this gene detected non-germline bands in Southern blot analyses of tumor DNA, thereby demonstrating the disruption of this gene by the t(7;17).; Genomic DNA in the breakpoint region on chromosome 17 was isolated by inverse PCR, and its sequence matched the sequence of a chromosome 17 BAC. Using this sequence data, a second novel gene encoding a zinc finger protein was identified. RT-PCR amplified a tumor-specific fusion transcript comprised of the 5′ end of the chromosome 7 gene and the 3 ′ end of the chromosome 17 gene. Furthermore, Northern blot analysis detected a corresponding tumor-specific transcript. Because the translocation generates an in-frame fusion of two previously undescribed zinc finger proteins, we refer to the chromosomes 7 and 17 genes as JAZF1 (J&barbelow;uxtaposed with A&barbelow;nother Z&barbelow;inc F&barbelow;inger 1) and JJAZ1 (J&barbelow;oined with JAZF1 1), respectively.; The two genes are widely expressed in most human tissues. JAZF1 is distributed throughout cells while the JAZF1/JJAZ1 fusion protein and presumably JJAZ1 localize exclusively to the nucleus. These novel zinc finger proteins may therefore act as transcription factors. A survey of endometrial stromal tumors by RT-PCR and FISH indicates that this genetic alteration is not limited to LG-ESS. It is present in monophasic endometrial stromal tumors of all grades and two biphasic endometrial tumors. The characterization of JAZF1, JJAZ1, and the JAZF1/JJAZ1 fusion gene will hopefully lead to an understanding of the oncogenesis of endometrial stromal tumors.