Cytogenetic and molecular profile of endometrial stromal sarcoma

Abstract

Recent cytogenetic and molecular investigations have improved our understanding of endometrial stromal tumors, including sarcomas (ESS), and helped redefine their classification into more pathogenetically meaningful categories. Because much more can be gained through such studies, we add information on another 22 ESS examined by karyotyping, PCR analysis, expression array analysis, and transcriptome sequencing. In spite of the known preference for certain pathogenetic pathways, we found considerable genetic heterogeneity in high-grade (HG) as well as in low-grade (LG) ESS. Not all HG tumors showed a YWHAE-NUTM chimeric transcript and as many as six LGESS showed no hitherto known ESS-related fusions. Among the transcripts identified by transcriptome sequencing and verified by Sanger sequencing, new variants of ZC3H7-BCOR and its reciprocal BCOR-ZC3H7 were identified as was involvement of the CREBBP and MLLT4 genes (both well known leukemia-related genes) in two new fusions. FISH analysis identified a known EPC1-PHF1 fusion which led to the identification of a new variant at the molecular level. The fact that around 70 genes were found differentially expressed, by microarray analysis, when comparing LGESS showing ESS-related fusions with LGESS without such transcripts, underscores the biochemical importance of the observed genetic heterogeneity and hints that new subgroups/entities in LGESS still remain undiscovered.

BCOR is a robust diagnostic immunohistochemical marker of genetically diverse high-grade endometrial stromal sarcoma, including tumors exhibiting variant morphology

“…Our findings demonstrate that BCOR expression is present in 50% of BCOR -rearranged high-grade endometrial stromal sarcomas and ZC3H7B-BCOR fusion was recently described in an uncommon group of endometrial stromal sarcomas (7, 28). In a previous study, we described the unique histologic features of this tumor which significantly overlap with myxoid leiomyosarcoma.…”

Molecular biomarkers for uterine leiomyosarcoma and endometrial stromal sarcoma

“…Further studies have shown that the PHF1 gene from chromosomal band 6p21 recombined with JAZF1 , EPC1 , MEAF6 or BRD8 , which encode the proteins involved in regulation of protein acetylation and/or histone acetyltransferase activity . All these fusions in ESS combined genes are involved in transcriptional regulation; that is, polycomb group complex‐mediated aberration methylation/acetylation; hence, their presumed oncogenic effects may be involved in the pathogenesis of ESS …”

“…53 All these fusions in ESS combined genes are involved in transcriptional regulation; that is, polycomb group complex-mediated aberration methylation/acetylation; hence, their presumed oncogenic effects may be involved in the pathogenesis of ESS. 52 Currently, ESS is considered to be a tumor with molecular genetic heterogeneity in gene rearrangement. Representative fusion T A B L E 2 Gene expression patterns of primary and metastatic lesions in patients and in vivo with distant metastatic u-LMS…”

Novel EPC1 gene fusions in endometrial stromal sarcoma

“…1 As its name implies, most tumors originate from the uterus; however, a subset arise from extra-uterine locations associated with endometriosis. 1 As its name implies, most tumors originate from the uterus; however, a subset arise from extra-uterine locations associated with endometriosis.…”