Fusion of the ZC3H7B and BCOR genes in endometrial stromal sarcomas carrying an X;22‐translocation

Abstract

Endometrial stromal sarcomas (ESS) are genetically heterogeneous uterine tumors in which a JAZF1-SUZ12 chimeric gene resulting from the chromosomal translocation t(7;17)(p15;q21) as well as PHF1 rearrangements (in chromosomal band 6p21) with formation of JAZF1-PHF1, EPC1-PHF1, and MEAF6-PHF1 chimeras have been described. Here, we investigated two ESS characterized cytogenetically by the presence of a der(22)t(X;22)(p11;q13). Whole transcriptome sequencing one of the tumors identified a ZC3H7-BCOR chimeric transcript. Reverse transciptase-PCR with the ZC3H7B forward and BCOR reverse primer combinations confirmed the presence of a ZC3H7-BCOR chimeric transcript in both ESS carrying a der(22)t(X;22) but not in a control ESS with t(1;6) and the MEAF6-PHF1 fusion. Sequencing of the amplified cDNA fragments showed that in both cases ESS exon 10 of ZC3H7B (from 22q13; accession number NM_017590 version 4) was fused to exon 8 of BCOR (from Xp11; accession number NM_001123385 version 1). Reciprocal multiple BCOR-ZC3H7B cDNA fragments were amplified in only one case suggesting that ZC3H7B-BCOR, on the der(22)t(X;22), is the pathogenetically important fusion gene. The putative ZC3H7B-BCOR protein would contain the tetratricopeptide repeats and LD motif from ZC3H7B and the AF9 binding site (1093-1233aa), the 3 ankyrin repeats (1410-1509 aa), and the NSPC1 binding site of BCOR. Although the presence of these motifs suggests various functions of the chimeric protein, it is possible that its most important role may be in epigenetic regulation. Whether or not the (patho)genetic subsets JAZF1-SUZ12, PHF1 rearrangements, and ZC3H7B-BCOR correspond to any phenotypic, let alone clinically important, differences in ESS remain unknown.

Comparison between Karyotyping-FISH-Reverse Transcription PCR and RNA- Sequencing-Fusion Gene Identification Programs in the Detection of KAT6A-CREBBP in Acute Myeloid Leukemia

“…We, too, have in previous studies analyzed RNA-Seq data using the FusionMap program finding that it identified fusion genes that corresponded well with the available cytogenetic information and that were biologically significant [23], [24], [25], [26], [27], [28]. The present study, on the other hand, shows that although the same approach detected hundreds (FusionMap) or tens (FusionFinder) of fusion genes, the programs failed to detect the biologically important KAT6A-CREBBP fusion gene although it was manually retrievable from the raw sequencing data.…”

“…We and others have used combinations of cytogenetics and RNA-seq to detect the “primary” fusion genes of neoplasms carrying only one or a few chromosomal rearrangements. This approach was used to identify the WWTR1-CAMTA1 and YWHAE-FAM22A/B chimeric genes in epithelioid hemangioendothelioma and high-grade endometrial stromal sarcomas, respectively [21], [22], ZC3H7-BCOR in endometrial stromal sarcomas [23], IRF2BP2-CDX1 in a mesenchymal chondrosarcoma [24], and EWSR1-YY1 in a subset of mesotheliomas [25]. In hematologic malignancies, an NFIA-CBFA2T3 ( NFIA is located in 1p31) chimeric transcript was found in an acute erythroid leukemia with the translocation t(1;16)(p31;q24) [26], the ZMYND8-RELA fusion was detected in a congenital acute erythroid leukemia carrying a t(11;20)(p11;q13) translocation [27], and a cryptic FUS/ERG fusion gene was found in an acute myeloid leukemia with a rather complex karyotype [28].…”

Endometrial stromal tumours revisited: an update based on the 2014 WHO classification

“…The most common rearrangement, t(7;17)(p15;q21), results in JAZF1-SUZ12 gene fusion 59. Other gene fusions include JAZF1-PHF1 ( figure 2I ) , and the much less common EPC1-PHF1, MEAF6-PHF1 ,60 61 ZC3H7-BCOR 62 and MBTD1-CXorf67 63. Molecular testing, however, is not routinely performed but may be helpful when dealing with cases of unusual location or morphology.…”

Practical issues related to uterine pathology: endometrial stromal tumors

“…34 Two additional translocations have been described in ESSs, t(X;22) (p11;q13) and t(X ;17) (p11.2;q21.33) associated with a ZC3H7B-BCOR fusion and a MBTD1-CXorf67 fusion, respectively. 35,36 Although endometrial stromal tumors are genetically heterogeneous, the different genes involved in low-grade ESS are functionally related (PHF1, SUZ12, EPC1, MBTD1), being members of the polycomb gene family. Of interest, ZC3H7B-BCOR, MEAF6-PHF1, and EPC1-PHF1 fusions were also identified in ossifying fibromyxoid tumors and JAZ1-PFH1 in an ossifying sarcoma of the heart.…”