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Abstract：
Birt-Hogg-Dubé (BHD) syndrome is associated with an increased risk of multifocal renal tumors, including hybrid oncocytic tumor (HOT) and chromophobe renal cell carcinoma (chRCC). HOT exhibits heterogenous histologic features overlapping with chRCC and benign renal oncocytoma, posing challenges in diagnosis of HOT and renal tumor entities resembling HOT. In this study, we performed integrative analysis of bulk and single-cell RNA sequencing data from renal tumors and normal kidney tissues, and nominated candidate biomarkers of HOT, L1CAM, and LINC01187 , which are also lineage-specific markers labeling the principal cell and intercalated cell lineages of the distal nephron, respectively. Our findings indicate the principal cell lineage marker L1CAM and intercalated cell lineage marker LINC01187 to be expressed mutually exclusively in a unique checkered pattern in BHD-associated HOTs, and these 2 lineage markers collectively capture the 2 distinct tumor epithelial populations seen to co-exist morphologically in HOTs. We further confirmed that the unique checkered expression pattern of L1CAM and LINC01187 distinguished HOT from chRCC, renal oncocytoma, and other major and rare renal cell carcinoma subtypes. We also characterized the histopathologic features and immunophenotypic features of oncocytosis in the background kidney of patients with BHD, as well as the intertumor and intratumor heterogeneity seen within HOT. We suggest that L1CAM and LINC01187 can serve as stand-alone diagnostic markers or as a panel for the diagnosis of HOT. These lineage markers will inform future studies on the evolution and interaction between the 2 transcriptionally distinct tumor epithelial populations in such tumors.
摘要：
Birt-Hogg-Dubé（BHD）综合征与多灶性肾脏肿瘤的风险增加有关，包括杂合嗜酸细胞瘤（HOT）和肾嫌色细胞癌（chRCC）。HOT表现出与chRCC和良性肾嗜酸细胞瘤重叠的异质性组织学特征，对HOT和类似HOT的肾肿瘤实体的诊断提出了挑战。在这项研究中,我们对来自肾肿瘤和正常肾组织的大量和单细胞RNA测序数据进行了综合分析，并提名了HOT的候选生物标志物，L1CAM,和LINC01187，它们也是标记远端肾单位的主要细胞和插入细胞谱系的谱系特异性标记，分别。我们的发现表明，主要细胞谱系标记L1CAM和插入的细胞谱系标记LINC01187在BHD相关的HOT中以独特的方格模式相互排他地表达，并且这2个谱系标记共同捕获在HOT中形态学上共存的2个不同的肿瘤上皮群体。我们进一步证实，L1CAM和LINC01187的独特方格表达模式区分HOT和chRCC，肾嗜酸细胞瘤,和其他主要和罕见的肾细胞癌亚型。我们还描述了BHD患者背景肾脏中肿瘤细胞增多症的组织病理学特征和免疫表型特征，以及HOT中看到的肿瘤间和肿瘤内异质性。我们建议L1CAM和LINC01187可以作为独立的诊断标记或作为诊断HOT的小组。这些谱系标记将为此类肿瘤中2种转录上不同的肿瘤上皮群体之间的进化和相互作用的未来研究提供信息。
