Frequent fusion of the <em>JAZF1</em> and <em>JJAZ1</em> genes in endometrial stromal tumors
Abstract
Endometrial stromal tumors are divided into three types: benign stromal nodules, endometrial stromal sarcomas, and undifferentiated endometrial sarcomas. A variety of cytogenetic abnormalities involving chromosome 7 have been reported in endometrial stromal sarcomas, including a recurrent t(7;17)(p15;q21). We have identified two zinc finger genes, which we have termed JAZF1 and JJAZ1, at the sites of the 7p15 and 17q21 breakpoints. Analyses of tumor RNA indicate that a JAZF1/JJAZ1 fusion is present in all types of endometrial stromal tumors; however, the fusion appears to be rarer among endometrial stromal sarcomas that would be considered high-grade according to certain classification schemes. These findings suggest that the less malignant endometrial stromal tumors may evolve toward more malignant types, but that some endometrial stromal sarcomas with relatively abundant mitotic activity may compose a biologically distinct group.
Endometrial stromal tumors of the uterus constitute a spectrum of neoplasms that exhibit varying degrees of malignancy and can present a number of challenges with respect to diagnosis and classification (1). Stromal nodules lie at the benign end of this spectrum of neoplasms. These nodules consist of well-circumscribed tumors composed of uniform cells resembling those of normal endometrial stroma during the proliferative phase of the menstrual cycle. Endometrial stromal sarcomas (ESSs) are malignant neoplasms that occupy the middle of the spectrum and are histologically similar to stromal nodules except for infiltration of the myometrium and/or vascular invasion. Tumors that depart significantly in histologic appearance from normal endometrial stroma are referred to as undifferentiated endometrial sarcomas (or undifferentiated uterine sarcomas) and represent the most malignant end of this tumor spectrum.
In the older literature, all malignant endometrial stromal tumors were categorized as ESSs and were subclassified into low-grade and high-grade types (2, 3). High-grade ESSs were distinguished from low-grade ESSs by an increased frequency of mitoses (>10 per high power microscopic field) and were generally assumed to have a worse prognosis. More recently, it has been argued that the number of mitoses within ESSs is largely irrelevant to outcome, which is said to be almost exclusively a function of stage at diagnosis (4–6).
Diagnosis and classification of endometrial stromal tumors has until now been based primarily on histologic criteria. In recent years, specific genetic alterations identified in different types of human tumors have provided useful diagnostic markers, led to insights into the basic biology of both neoplastic and normal tissues, and increasingly contributed to the development of rational forms of cancer therapy (7–9). With these considerations in mind, we have characterized the DNA and genes surrounding the breakpoints of a recurrent chromosomal translocation, the t(7;17)(p15;q21), reported in several cases of low-grade ESS (10–13). We have found that recombination at these breakpoints results in fusion of two previously unknown genes, which we have termed JAZF1 and JJAZ1. Fusion of these genes appears to be common in low-grade ESSs but is not limited to these neoplasms and can be found in other types of endometrial stromal tumors as well. However, the incidence of this fusion appears to be reduced among ESSs that might be classified as high-grade.
Acknowledgments
We thank Megan Smith for valuable technical assistance. This work was supported by the National Foundation for Cancer Research and National Institutes of Health-National Cancer Institute Grant CA-85995.
Abbreviations
ESS | endometrial stromal sarcoma |
YAC | yeast artificial chromosome |
BAC | bacterial artificial chromosome |
EST | expressed sequence tag |
FISH | fluorescence in situ hybridization |
RT-PCR | reverse transcription–PCR |
STS | sequence-tagged site |
I-PCR | inverse PCR |
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