Dal Cin P, Sklar J. Molecular analysis of the JAZF1–JJAZ1 gene fusion by RT–PCR and fluorescence in situ hybridization in endometrial stromal neoplasms

Duke University, Durham, North Carolina, United States
American Journal of Surgical Pathology (Impact Factor: 5.15). 02/2007; 31(1):65-70. DOI: 10.1097/01.pas.0000213327.86992.d1
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Nonrandom cytogenetic abnormalities of chromosomes 6, 7, and 17 have been reported within low-grade endometrial stromal sarcomas (LGESSs), and among these abnormalities, the t(7;17)(p15;q21) is the most common aberration described. Previously we had shown that this translocation joins 2 genes, JAZF1 and JJAZ1, located on chromosomes 7 and 17, respectively. To determine the frequency of the t(7;17), we analyzed 4 stromal nodules and 24 LGESS by both reverse transcriptase-polymerase chain reaction and fluorescence in situ hybridization (FISH). In addition, we examined 4 cases of highly cellular leiomyoma, a benign morphologic mimic of LGESS. Overall, evidence for the JAZF1-JJAZ1 fusion was found in 60% of endometrial stromal neoplasms analyzed (8/16 ESS and 4/4 stromal nodules). One LGESS demonstrated only rearrangement of 7p15 by FISH analysis and karyotypic analysis of this case showed t(6;7)(p21;p15). The fusion was not detected in any highly cellular leiomyomas. Our data suggest that the JAZF1-JJAZ1 fusion is a frequent, although nonuniform, feature of endometrial stromal neoplasia, irrespective of benign versus malignant classification and smooth muscle differentiation. In addition, the detection of the fusion by reverse transcriptase-polymerase chain reaction or FISH for JJAZ1 at 7p15 may be diagnostically useful.

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Available from: Paola Dal Cin
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    • "Molecular studies of the t(7;17) have shown that the translocation leads to the fusion of two zinc finger genes, JAZF1 and SUZ12 (also named JJAZ1) [5]. Subsequent studies of larger tumor series using RT-PCR and fluorescence in situ hybridization (FISH) have shown the occurrence of the JAZF1/SUZ12 fusion gene not only in ESS but also in endometrial stromal nodules and, less frequently, in undifferentiated endometrial sarcomas [6], [7], [8], [9]. "
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    ABSTRACT: Rearrangement of chromosome band 6p21 is recurrent in endometrial stromal sarcoma (ESS) and targets the PHF1 gene. So far, PHF1 was found to be the 3' partner in the JAZF1-PHF1 and EPC1-PHF1 chimeras but since the 6p21 rearrangements involve also other chromosomal translocation partners, other PHF1-fusions seem likely. Here, we show that PHF1 is recombined with a novel fusion partner, MEAF6 from 1p34, in an ESS carrying a t(1;6)(p34;p21) translocation as the sole karyotypic anomaly. 5'-RACE, RT-PCR, and sequencing showed the presence of an MEAF6-PHF1 chimera in the tumor with exon 5 of MEAF6 being fused in-frame to exon 2 of PHF1 so that the entire PHF1 coding region becomes the 3' terminal part of the MEAF6-PHF1 fusion. The predicted fusion protein is composed of 750 amino acids and contains the histone acetyltransferase subunit NuA4 domain of MEAF6 and the tudor, PHD zinc finger, and MTF2 domains of PHF1. Although the specific functions of the MEAF6 and PHF1 proteins and why they are targeted by a neoplasia-specific gene fusion are not directly apparent, it seems that rearrangement of genes involved in acetylation (EPC1, MEAF6) and methylation (PHF1), resulting in aberrant gene expression, is a common theme in ESS pathogenesis.
    Full-text · Article · Jun 2012 · PLoS ONE
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    • "In this study, the translocation was found in 7/7 cases of ESS, 3/3 cases of endometrial stromal nodule, but only in 3/7 cases of UES. These results have been repeated in subsequent larger studies, with translocations detected in 8/16 cases of ESS and 4/4 ESN [26], and 6/12 cases of ESS but only 1/9 cases of UES [27]. The presence of the translocation in ESN raises the possibility that ESS may arise from a progression from a benign stromal proliferation. "
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    ABSTRACT: Uterine sarcomas are a group of rare tumours that provide considerable challenges in their treatment. Radiological diagnosis prior to hysterectomy is difficult, with the diagnosis frequently made post-operatively. Current staging systems have been unsatisfactory, although a new FIGO staging system specifically for uterine sarcomas has now been introduced, and may allow better grouping of patients according to expected prognosis. While the mainstay of treatment of early disease is a total abdominal hysterectomy, it is less clear whether routine oophorectomy or lymphadenectomy is necessary. Adjuvant pelvic radiotherapy may improve local tumour control in high risk patients, but is not associated with an overall survival benefit. Similarly there is no good evidence for the routine use of adjuvant chemotherapy. For advanced leiomyosarcoma, newer chemotherapy agents including gemcitabine and docetaxel, and trabectedin, offer some promise, while hormonal therapies appear to be more useful in endometrial stromal sarcoma. Novel targeted agents are now being introduced for sarcomas, and uterine sarcomas, and show some indications of activity. Non-pharmacological treatments, including surgical metastatectomy, radiofrequency ablation, and CyberKnife(®) radiotherapy, are important additions to systemic therapy for advanced metastatic disease.
    Full-text · Article · Apr 2011 · European journal of radiology
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    • "The studies with RT-PCR only can give false-positive results due to PCR contamination. FISH may be useful as a complementary technique to exclude the possibility of false positive contamination of cases by RT-PCR [44]. Although the JAZF1/JJAZ1 fusion gene seems to be the major molecular alterations in endometrial stromal sarcomas, there is some evidence for alternative pathways in the development of endometrial stromal sarcomas. "
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    ABSTRACT: Molecular profiling of endometrial neoplasms reveals genetic changes in endometrial carcinomas that support the dualistic model, in which type I carcinomas are estrogen-dependent, low grade lesions and type II carcinomas are nonestrogen dependent and high grade. The molecular changes in type I endometrial carcinomas include mutations in PTEN, PIK3CA, KRAS, and beta-catenin, along with microsatellite instability, whereas type II endometrial carcinomas are characterized by genetic alterations in p53, HER2/neu, p16, and E-cadherin. For endometrial neoplasms with a malignant mesenchymal component, C-MYC mutations and loss of heterozygosity are frequently seen in carcinosarcomas, and a fusion gene, JAZF1/JJAZ1, is distinctive for endometrial stromal sarcoma. In addition, p53 mutations may play an important role in tumorigenesis of undifferentiated endometrial sarcoma. These molecular changes can help in the diagnosis of endometrial neoplasms, as well as form the basis of molecular targeted therapy.
    Full-text · Article · Mar 2010 · Obstetrics and Gynecology International
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