Department of Pathology and Diagnostic, University of Verona, Verona, Italy.
Mod Pathol. 2011 Oct;24(10):1313-9. doi: 10.1038/modpathol.2011.93. Epub 2011 May 20.
Cathepsin K is a protease whose expression is driven by microphthalmia transcription factor (MITF) in osteoclasts. TFE3 and TFEB are members of the same transcription factor subfamily as MITF and all three have overlapping transcriptional targets. We have shown that all t(6;11) renal cell carcinomas, which harbor an Alpha-TFEB gene fusion, as well as a subset of the Xp11 translocation renal carcinomas, which harbor various TFE3 gene fusions, express cathepsin K, while no other common renal carcinoma does. We have hypothesized that overexpression of TFEB or certain TFE3 fusion proteins function like MITF in these neoplasms, and thus activate cathepsin K expression. However, the expression of cathepsin K in specific genetic subtypes of Xp11 translocation carcinomas, as well as alveolar soft part sarcoma, which harbors the same ASPSCR1-TFE3 gene fusion as some Xp11 translocation carcinomas, has not been addressed. We performed immunohistochemistry for cathepsin K on 14 genetically confirmed t(X;1)(p11;q21) carcinomas, harboring the PRCC-TFE3 gene fusion; eight genetically confirmed t(X;17)(p11;q25) carcinomas, harboring the ASPSCR1-TFE3 gene fusion; and 18 alveolar soft part sarcomas (12 genetically confirmed), harboring the identical ASPSCR1-TFE3 gene fusion. All 18 alveolar soft part sarcomas expressed cathepsin K. In contrast, all eight ASPSCR1-TFE3 carcinomas were completely negative for cathepsin K. However, 12 of 14 PRCC-TFE3 carcinomas expressed cathepsin K. Expression of cathepsin K distinguishes alveolar soft part sarcoma from the ASPSCR1-TFE3 carcinoma, harboring the same gene fusion. The latter can be useful diagnostically, especially when alveolar soft part sarcoma presents in an unusual site (such as bone) or with clear cell morphology, which raises the differential diagnosis of metastatic ASPSCR1-TFE3 renal cell carcinoma. The difference in expression of cathepsin K between the PRCC-TFE3 and ASPSCR1-TFE3 carcinomas, together with the observed clinical differences between these subtypes of Xp11 translocation carcinomas, suggests the possibility of functional differences between these two related fusion proteins.
组织蛋白酶 K 是一种由破骨细胞中的小眼畸形转录因子 (MITF) 驱动表达的蛋白酶。TFE3 和 TFEB 是与 MITF 同一家族的转录因子成员，并且它们都具有重叠的转录靶标。我们已经表明，所有携带 Alpha-TFEB 基因融合的 t(6;11) 肾细胞癌以及携带各种 TFE3 基因融合的部分 Xp11 易位肾细胞癌都表达组织蛋白酶 K，而其他常见的肾细胞癌则没有。我们假设 TFEB 或某些 TFE3 融合蛋白的过度表达在这些肿瘤中像 MITF 一样起作用，从而激活组织蛋白酶 K 的表达。然而，特定遗传亚型的 Xp11 易位癌以及肺泡软组织肉瘤中组织蛋白酶 K 的表达尚未得到解决，肺泡软组织肉瘤与一些 Xp11 易位癌一样携带相同的 ASPSCR1-TFE3 基因融合。我们对 14 例经基因证实的携带 PRCC-TFE3 基因融合的 t(X;1)(p11;q21) 癌、8 例经基因证实的携带 ASPSCR1-TFE3 基因融合的 t(X;17)(p11;q25) 癌以及 18 例（12 例经基因证实）肺泡软组织肉瘤进行了组织蛋白酶 K 的免疫组织化学染色。所有 18 例肺泡软组织肉瘤均表达组织蛋白酶 K。相比之下，所有 8 例 ASPSCR1-TFE3 癌均完全阴性。然而，14 例 PRCC-TFE3 癌中有 12 例表达了组织蛋白酶 K。组织蛋白酶 K 的表达将肺泡软组织肉瘤与携带相同基因融合的 ASPSCR1-TFE3 癌区分开来。后者在诊断上可能很有用，尤其是当肺泡软组织肉瘤出现在不常见的部位（如骨骼）或具有透明细胞形态时，这会提高转移性 ASPSCR1-TFE3 肾细胞癌的鉴别诊断。PRCC-TFE3 和 ASPSCR1-TFE3 癌之间组织蛋白酶 K 表达的差异，以及 Xp11 易位癌这两种亚型之间观察到的临床差异，表明这两种相关融合蛋白之间存在功能差异的可能性。
