Molecular Detection of JAZF1-JJAZ1 Gene Fusion in Endometrial Stromal Neoplasms with Classic and Variant Histology

Abstract

Endometrial stromal tumors (ESTs), including low-grade endometrial stromal sarcomas (LGESSs) and endometrial stromal nodules (ESNs) of classic histology, exhibit characteristic morphologic features and contain the nonrandom t(7;17)(p15; q21), which results in the fusion of two novel genes, JAZF1 and JJAZ1. ESTs may pose diagnostic challenges when they involve extrauterine sites, present as metastases, or display variant histologic appearances. The aim of this study was to evaluate the frequency of the JAZF1-JJAZ1 gene fusion among primary uterine, metastatic, and primary extrauterine ESTs of various histologic types and its role as a possible diagnostic adjunct. Using a nonnested reverse transcriptase-polymerase chain reaction approach, we assayed for JAZF1-JJAZ1 gene fusion transcripts in 10 cases with available fresh-frozen tissue. These included five primary uterine (two classic, one mixed smooth muscle, and one epithelioid LGESS; one classic ESN), four metastatic (two fibromyxoid, one classic, and one epithelioid LGESS), and one extrauterine (classic LGESS) tumor. The same primer set and assay conditions were used on five additional paraffin-embedded cases with adequate RNA, including three primary uterine (one fibromyxoid and one mixed smooth muscle LGESS; 1 mixed smooth muscle ESN) and two intraabdominal recurrent (two mixed smooth muscle LGESSs) ESTs. Two cellular leiomyomas and one ESS cell line (ESS-1) without the t(7;17) at the cytogenetic level were run in parallel as controls. JAZF1-JJAZ1 gene fusion transcripts were detected in five (33%) of 15 ESTs, including three of eight primary uterine, one of four metastatic, one of one extrauterine, and none of two recurrent cases. Most ESTs of classic histology showed evidence of JAZF1-JJAZ1 fusion (4 of 5 cases), whereas only one mixed smooth muscle ESN of 10 variant cases was positive. Positivity for JAZF1-JJAZ1 fusion transcripts was found in four of 10 fresh-frozen samples and in one of five paraffin-embedded ESTs. The control specimens were all negative. In conclusion, our data suggest that ESTs are genetically heterogeneous, with the prevalence of the JAZF1-JJAZ1 fusion being highest among ESTs of classic histology. Hence, the diagnostic utility of a JAZF1-JJAZ1 fusion transcript assay in ESTs may be limited to the classic histologic subset.

Coincident expression of β-catenin and cyclin D1 in endometrial stromal tumors and related high-grade sarcomas

“…2 Our results showing a high prevalence of JAZF1-JJAZ1 among endometrial stromal nodules (66%) are consistent with the several reports dealing with endometrial stromal nodule cases. Regarding endometrial stromal nodule, JAZF1-JJAZ1 gene fusion was detected in all three cases reported by Koontz et al,20 in the two cases reported by Huang et al, 31 and in all four cases reported by Nucci et al 28 As for endometrial stromal tumors with sex cordlike differentiation, there have been two cases reported in the literature in which JAZF1-JJAZ1 fusion was detected. 29,30 In our study, one of the two cases of endometrial stromal nodule with sex cordlike differentiation was positive for the JAZF1-JJAZ1 fusion transcript, supporting the idea that genetic heterogeneity exists among endometrial stromal tumors with variant histology.…”

“…29,30 In our study, one of the two cases of endometrial stromal nodule with sex cordlike differentiation was positive for the JAZF1-JJAZ1 fusion transcript, supporting the idea that genetic heterogeneity exists among endometrial stromal tumors with variant histology. 31 On the basis of review of the literature and our study, we have hypothesized a simplified model for the histogenesis of endometrial stromal tumors and related high-grade sarcomas (Figure 4). It is commonly accepted that endometrial stromal nodule and low-grade endometrial stromal sarcoma belong to the same category featuring endometrial stromal differentiation.…”

Practical issues related to uterine pathology: endometrial stromal tumors

“…The most common genetic aberration identified in ESNs, which is similarly identified in LGESS (discussed later), is t(7;17)(p15;q21). [9][10][11][12] Recognition as an Endometrial Stromal Neoplasm (Biopsy/Curettage Specimen)…”

“…29 The most common genetic abnormality in low-grade ESS is t(7;17)(p15;q21), resulting in the fusion of JAZF1 and SUZ12(JJAZ1) genes at 7p15 and 17q21, respectively. [9][10][11][12]30,31 The reported frequency of JAZF1-JJAZ1 fusion has been detected in~48% of low-grade ESS. 32 The second most frequent abnormality is t(6;7)(p21;p15), a so-called variant translocation of the t(7;17), because of the involvement of 7p15 and 6p21 instead of 17q21 resulting in a JAZF1-PHF1 fusion gene.…”

Endometrial sarcomas: an immunohistochemical and JAZF1 re-arrangement study in low-grade and undifferentiated tumors

“…[4][5][6][7] Low-grade endometrial stromal sarcoma is also characterized by chromosomal translocations in a subset of cases, most commonly t(7;17)(p15;q21) involving zincfinger genes, JAZF1 and SUZ1. [8][9][10][11][12][13][14] The WHO identifies undifferentiated endometrial sarcoma as displaying marked cellular atypia and lacking morphologic evidence of an endometrial stromal phenotype. Older grading systems, however, allowed for a category of endometrial sarcomas with greater atypia than low-grade endometrial stromal sarcoma, whereas retaining some resemblance to endometrial stroma.…”