TFE3-Fusion Variant Analysis Defines Specific Clinicopathologic Associations Among Xp11 Translocation Cancers.
TFE3-Fusion Variant Analysis Defines Specific Clinicopathologic Associations Among Xp11 Translocation Cancers.
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DOI：
10.1097/pas.0000000000000631
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发表时间：
2016-06
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影响因子：
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通讯作者：
Antonescu CR
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作者：
Argani P;Zhong M;Reuter VE;Fallon JT;Epstein JI;Netto GJ;Antonescu CR
Xp 11易位癌症包括Xp 11易位肾细胞癌（RCC）、Xp 11易位血管周围上皮样细胞肿瘤（PEComa）和黑色素性Xp 11易位肾癌。在Xp 11易位癌中，TFE 3的致癌激活是由TFE 3与许多不同基因伴侣的融合驱动的，然而，个体融合变体对Xp 11易位癌的特定临床病理特征的影响尚未得到很好的确定。在这项研究中，我们分析了60 Xp 11易位癌荧光原位杂交（FISH）使用自定义BAC探针，以建立他们的TFE 3融合基因的合作伙伴。在5例病例中，还使用RNA测序（RNA-seq）来进一步表征融合转录物。60例Xp 11易位癌包括47例Xp 11易位RCC、8例Xp 11易位PEComa和5例黑色素性Xp 11易位肾癌。在53/60例（88%）病例中确定了融合伴侣，包括18例SFPQ（PSF）、16例PRCC、12例ASPSCR 1（ASPL）、6例NONO和1例DVL 2。我们提供了NONO-TFE 3 RCC的第一个形态学描述，它经常显示亚核空泡，导致独特的基底上核栅栏。类似的亚核空泡化也是SFPQ-TFE 3 RCC的特征，与透明细胞乳头状RCC形成重叠特征。我们还描述了第一个肾细胞癌与DVL 2-TFE 3基因融合，除了一个肾外色素性PEComa与NONO-TFE 3基因融合。此外，在SFPQ-TFE 3、NONO-TFE 3、DVL 2-TFE 3和ASPL-TFE 3基因融合的肿瘤中，RCC几乎总是PAX 8阳性，组织蛋白酶K阴性，而间充质对应物（Xp 11易位PEComa、黑色素性Xp 11易位肾癌和腺泡状软组织肉瘤）是PAX 8阴性，组织蛋白酶K阳性。这些发现支持了这样一个概念，即尽管有相同的基因融合，但RCC与相应的间充质肿瘤不同，这可能是由于易位发生的细胞背景。我们证实了先前的数据显示，PRCC-TFE 3 RCC是唯一已知的Xp 11易位RCC分子亚型，其始终是组织蛋白酶K阳性。总之，我们的数据进一步扩展了具有特异性TFE 3基因融合的癌症的临床病理学特征，并且应该允许得出更有意义的临床病理学关联。
Xp11 translocation cancers include Xp11 translocation renal cell carcinoma (RCC), Xp11 translocation perivascular epithelioid cell tumor (PEComa), and melanotic Xp11 translocation renal cancer. In Xp11 translocation cancers, oncogenic activation of TFE3 is driven by the fusion of TFE3 with a number of different gene partners, however, the impact of individual fusion variant on specific clinicopathologic features of Xp11 translocation cancers has not been well defined. In this study, we analyze 60 Xp11 translocation cancers by fluorescence in situ hybridization (FISH) using custom BAC probes to establish their TFE3 fusion gene partner. In 5 cases RNA sequencing (RNA-seq) was also used to further characterize the fusion transcripts. The 60 Xp11 translocation cancers included 47 Xp11 translocation RCC, 8 Xp11 translocation PEComas, and 5 melanotic Xp11 translocation renal cancers. A fusion partner was identified in 53/60 (88%) cases, including 18 SFPQ (PSF), 16 PRCC, 12 ASPSCR1 (ASPL), 6 NONO, and 1 DVL2. We provide the first morphologic description of the NONO-TFE3 RCC, which frequently demonstrates sub-nuclear vacuoles leading to distinctive suprabasal nuclear palisading. Similar sub-nuclear vacuolization was also characteristic of SFPQ-TFE3 RCC, creating overlapping features with clear cell papillary RCC. We also describe the first RCC with a DVL2-TFE3 gene fusion, in addition to an extrarenal pigmented PEComa with a NONO-TFE3 gene fusion. Furthermore, among neoplasms with the SFPQ-TFE3, NONO-TFE3, DVL2-TFE3 and ASPL-TFE3 gene fusions, the RCC are almost always PAX8-positive, cathepsin K-negative by immunohistochemistry, whereas the mesenchymal counterparts (Xp11 translocation PEComas, melanotic Xp11 translocation renal cancers, and alveolar soft part sarcoma) are PAX8-negative, cathepsin K-positive. These findings support the concept that despite an identical gene fusion, the RCCs are distinct from the corresponding mesenchymal neoplasms, perhaps due to the cellular context in which the translocation occurs. We corroborate prior data showing that the PRCC-TFE3 RCC are the only known Xp11 translocation RCC molecular subtype which is consistently cathepsin K positive. In summary, our data expand further the clinicopathologic features of cancers with specific TFE3 gene fusions, and should allow for more meaningful clinicopathologic associations to be drawn.