Identification of a novel, recurrent MBTD1‐CXorf67 fusion in low‐grade endometrial stromal sarcoma

Abstract

Endometrial stromal sarcomas (ESSs) are a genetically heterogeneous group of rare uterine neoplasms that are commonly driven by recurrent gene rearrangements. In conventional low-grade ESS, JAZF1-SUZ12, PHF1-JAZF1, EPC1-PHF1 and MEAF6-PHF1, and recently described ZC3H7-BCOR chimeric fusions have been reported in > 50% of cases. Conversely, oncogenic t(10;17)(q22;p13) translocation yields YWHAE-FAM22A/B chimeric proteins that are associated with histologically high-grade and clinically more aggressive ESS. Integrating whole-transcriptome paired-end RNA sequencing with fluorescence in situ hybridization (FISH) and banding cytogenetics, we identified MBTD1 (malignant brain tumor domain-containing 1) and CXorf67 (chromosome X open reading frame 67) as the genes involved in the novel reciprocal t(X;17)(p11.2;q21.33) translocation in two independent low-grade ESS of classical histology. The presence of the MBTD1-CXorf67 fusion transcript was validated in both cases using reverse-transcription polymerase chain reaction followed by Sanger sequencing. A specific FISH assay was developed to detect the novel t(X;17) translocation in formalin-fixed paraffin-embedded material, and resulted in identification of an additional low-grade ESS case positive for the MBTD1-CXorf67 fusion among 25 uterine stromal tumors [14 ESS and 11 undifferentiated endometrial sarcomas (UESs)] that were negative for JAZF1 and YWHAE rearrangements. Gene expression profiles of seven ESS (including three with YWHAE and two with JAZF1 rearrangements) and four UES without specific chromosomal aberrations indicated clustering of tumors with MBTD1-CXorf67 fusion together with low-grade JAZF1-associated ESS. The chimeric MBTD1-CXorf67 fusion identifies yet another cytogenetically distinct subgroup of low-grade ESS and offers the opportunity to shed light on the functions of two poorly characterized genes.

The JAZF1-SUZ12 fusion protein disrupts PRC2 complexes and impairs chromatin repression during human endometrial stromal tumorogenesis

“…Among these chromosomal abnormalities, t(7;17)(p15;q21), which results in an in frame fusion of the Jazf1 gene with Suz12 on chromosome 17 is the most common cytogenetic abnormalities [52]. Other translocations include the t(6;7)(p21;p15), which results in an in-frame fusion of Jazf1 to Phf1 [59]; the t(6;10)(p21;p11), which results in an Epc1 fused to Phf1 [58]; the t(1;6)(p34;p21), which results in an in-frame fusion of Meaf6 gene to Phf1 [59]; der(22)(X;22)(p11;q13) results in Zc3h7b in-frame joints to Bcor gene [60]; t(X;17)(p11;q21) results in Mbtd1 gene fuses to Cxorf67 [61]. If the fusion of in-frame remains unknown; t(10;17)(q22;p13) results in Ywhae gene in-frame joins to Fam22a or Fam22b ; this translocation is also known as 14-3-3 epsilon-FAM22A (FAM22B) [62].…”

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.…”