Clinicopathologic and Molecular Analysis of the TFEB Fusion Variant Reveals New Members of TFEB Translocation Renal Cell Carcinomas (RCCs) Expanding the Genomic Spectrum
Clinicopathologic and Molecular Analysis of the TFEB Fusion Variant Reveals New Members of TFEB Translocation Renal Cell Carcinomas (RCCs) Expanding the Genomic Spectrum
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TFEB 融合变体的临床病理学和分子分析揭示了 TFEB 易位肾细胞癌 (RCC) 的新成员，扩大了基因组谱
DOI：
10.1097/pas.0000000000001408
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发表时间：
2020-04-01
影响因子：
5.6
通讯作者：
Rao, Qiu
中科院分区：
文献类型：
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作者：
Xia, Qiu-Yuan;Wang, Xiao-Tong;Rao, Qiu
具有不同基因融合的XP11肾细胞癌（RCC）可能具有不同的临床病理特征。我们试图确定TFEB易位RCC中的变体融合。总共选择了31例TFEB RCC进行当前研究；使用融合探针在25例（81％，25/31）中鉴定出MALAT1-TFEB融合。 The remaining 6 cases (19%, 6/31) were further analyzed by RNA sequencing and 5 of them were detected with TFEB-associated gene fusions, including 2 ACTB-TFEB, 1 EWSR1-TFEB, 1 CLTC-TFEB, and 1 potential PPP1R10-TFEB (a paracentric inversion of the TFEB gene, consistent with "negative" TFEB split FISH result, and advising a potential检测TFEB基因重排时的诊断陷阱）。 5个融合转录本中的四个通过逆转录聚合酶链反应和桑格测序成功验证。从形态上讲，TFEB RCC的大约三分之一（29％，9/31）显示出典型的双相形态。其余三分之二的病例（71％，22/31）表现出非特异性形态，具有嵌套，类似薄片的或乳头状结构，类似于其他类型的肾脏肿瘤，例如透明细胞RCC，XP11 RCC，血管性上皮上皮细胞肿瘤（PECOMA）或乳头状肿瘤或乳头状肿瘤。尽管带有Malat1-TFEB融合的病例表现出可变的形态，但所有9例具有典型双相形态的病例都与Malat1-TFEB基因型有关。因此，典型的双相形态表明MALAT1-TFEB融合，而非典型的形态并未提示特定的融合类型。分离的或聚集的嗜酸性细胞是TFEB RCC中的共同特征，这可能是TFEB RCC的有用形态诊断线索。临床病理变量评估表明，坏死是与TFEB RCC侵略性行为相关的唯一形态学特征（p = 0.004）。总而言之，我们的研究扩大了TFEB RCC的基因组光谱和临床病理特征，并通过结合形态和多种分子技术来强调诊断的挑战以及该肿瘤的亚型的重要性。
Xp11 renal cell carcinoma (RCC) with different gene fusions may have different clinicopathologic features. We sought to identify variant fusions in TFEB translocation RCC. A total of 31 cases of TFEB RCCs were selected for the current study; MALAT1-TFEB fusion was identified in 25 cases (81%, 25/31) using fusion probes. The remaining 6 cases (19%, 6/31) were further analyzed by RNA sequencing and 5 of them were detected with TFEB-associated gene fusions, including 2 ACTB-TFEB, 1 EWSR1-TFEB, 1 CLTC-TFEB, and 1 potential PPP1R10-TFEB (a paracentric inversion of the TFEB gene, consistent with "negative" TFEB split FISH result, and advising a potential diagnostic pitfall in detecting TFEB gene rearrangement). Four of the 5 fusion transcripts were successfully validated by reverse transcription-polymerase chain reaction and Sanger sequencing. Morphologically, approximately one third (29%, 9/31) of TFEB RCCs showed typical biphasic morphology. The remaining two thirds of the cases (71%, 22/31) exhibited nonspecific morphology, with nested, sheet-like, or papillary architecture, resembling other types of renal neoplasms, such as clear cell RCC, Xp11 RCC, perivascular epithelioid cell tumor (PEComa), or papillary RCC. Although cases bearing a MALAT1-TFEB fusion demonstrated variable morphologies, all 9 cases featuring typical biphasic morphology were associated with MALAT1-TFEB genotype. Accordingly, typical biphasic morphology suggests MALAT1-TFEB fusion, whereas atypical morphology did not suggest the specific type of fusion. Isolated or clustered eosinophilic cells were a common feature in TFEB RCCs, which may be a useful morphology diagnostic clue for TFEB RCCs. Clinicopathologic variables assessment showed that necrosis was the only morphologic feature that correlated with the aggressive behavior of TFEB RCC (P=0.004). In summary, our study expands the genomic spectrum and the clinicopathologic features of TFEB RCCs, and highlights the challenges of diagnosis and the importance of subtyping of this tumor by combining morphology and multiple molecular techniques.