Identification of a novel, recurrent MBTD1-CXorf67 fusion in low-grade endometrial stromal sarcoma
Identification of a novel, recurrent MBTD1-CXorf67 fusion in low-grade endometrial stromal sarcoma
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DOI：
10.1002/ijc.28440
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发表时间：
2014-03-01
影响因子：
6.4
通讯作者：
Debiec-Rychter, Maria
中科院分区：
文献类型：
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作者：
Dewaele, Barbara;Przybyl, Joanna;Debiec-Rychter, Maria
子宫内膜间质肉瘤（ESS）是一组遗传异质性罕见的子宫肿瘤，通常由复发性基因重排驱动。在传统的低度ESS中，JAZF 1-SUZ 12、PHF 1-JAZF 1、EPC 1-PHF 1和MEAF 6-PHF 1以及最近描述的ZC 3 H7-BCOR嵌合融合体已在> 50%的病例中报道。相反，致癌t（10;17）（q22; p13）易位产生YWHAE-FAM 22 A/B嵌合蛋白，其与组织学上高级别和临床上更具侵袭性的ESS相关。我们发现MBTD 1（恶性脑肿瘤结构域包含1）和CXorf 67（染色体X开放阅读框67）作为参与经典组织学的两个独立的低度ESS中的新型相互t（X;17）（p11.2;q21.33）易位的基因。在这两种情况下，使用逆转录聚合酶链反应，然后通过桑格测序来验证MBTD 1-CXorf 67融合转录物的存在。开发了一种特异性FISH检测方法，用于检测福尔马林固定石蜡包埋材料中的新型t（X;17）易位，并在JAZF 1和YWHAE重排阴性的25例子宫间质瘤[14例ESS和11例未分化子宫内膜肉瘤（UES）]中鉴定出另一例MBTD 1-CXorf 67融合阳性的低级别ESS病例。七种ESS的基因表达谱（包括3例YWHAE和2例JAZF 1重排）和4例无特异性染色体畸变的UES表明，MBTD 1-CXorf 67融合的肿瘤与低级别JAZF 1相关ESS一起聚集。等级ESS，并提供了机会阐明两个特征不佳的基因的功能。
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.