基于新一代 RNA 测序的嫌色细胞肾细胞癌及相关嗜酸细胞瘤的生物标志物特征分析。
Next-generation RNA Sequencing-based Biomarker Characterization of Chromophobe Renal Cell Carcinoma and Related Oncocytic Neoplasms.
机构信息
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, Ann Arbor, MI, USA.
出版信息
Eur Urol. 2020 Jul;78(1):63-74. doi: 10.1016/j.eururo.2020.03.003. Epub 2020 Apr 13.
BACKGROUND
Renal cell carcinomas (RCCs) are a heterogeneous group of neoplasms. Recent sequencing studies revealed various molecular features associated with histologic RCC subtypes, including chromophobe renal cell carcinoma (ChRCC).
OBJECTIVE
To characterize the gene expression and biomarker signatures associated with ChRCC.
DESIGN, SETTING, AND PARTICIPANTS: We performed integrative analysis on RNA sequencing data available from 1049 RCC specimens from The Cancer Genome Atlas and in-house studies. Our workflow identified genes relatively enriched in ChRCC, including Forkhead box I1 (FOXI1), Rh family C glycoprotein (RHCG), and LINC01187. We assessed the expression pattern of FOXI1 and RHCG protein by immunohistochemistry (IHC) and LINC01187 mRNA by RNA in situ hybridization (RNA-ISH) in whole tissue sections representing a cohort of 197 RCC cases, including both primary and metastatic tumors.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
The FOXI1 and RHCG IHC staining, as well as the LINC01187 RNA-ISH staining, was evaluated in each case for intensity, pattern, and localization of expression.
RESULTS AND LIMITATIONS
All primary and metastatic classic ChRCCs demonstrated homogeneous positive labeling for FOXI1, RHCG proteins, and LINC01187 transcript. Unclassified RCC with oncocytic features, oncocytoma, and hybrid oncocytic tumor, as well as all but two cases of eosinophilic ChRCC also stained positive. Importantly, metastatic and primary RCC of all other subtypes did not demonstrate any unequivocal staining for FOXI1, RHCG, or LINC01187. In normal kidney, FOXI1, RHCG, and LINC01187 were detected in the distal nephron segment, specifically in intercalated cells. Two cases of eosinophilic ChRCC with focal expression of FOXI1 and LINC01187, and Golgi-like RHCG staining were found to contain MTOR gene mutations upon DNA sequencing.
CONCLUSIONS
We demonstrate a pipeline for the identification and validation of RCC subtype-specific biomarkers that can aid in the confirmation of cell of origin and may facilitate accurate classification and diagnosis of renal tumors.
PATIENT SUMMARY
FOXI1, RHCG, and LINC01187 are lineage-specific signature genes for chromophobe renal cell carcinoma.
背景
肾细胞癌（RCC）是一组异质性肿瘤。最近的测序研究揭示了与组织学 RCC 亚型相关的各种分子特征，包括嫌色细胞肾细胞癌（ChRCC）。
目的
描述与 ChRCC 相关的基因表达和生物标志物特征。
设计、环境和参与者：我们对来自癌症基因组图谱（TCGA）和内部研究的 1049 例 RCC 标本的 RNA 测序数据进行了综合分析。我们的工作流程确定了在 ChRCC 中相对富集的基因，包括叉头框 I1（FOXI1）、Rh 家族 C 糖蛋白（RHCG）和 LINC01187。我们通过免疫组织化学（IHC）评估了 FOXI1 和 RHCG 蛋白的表达模式，通过 RNA 原位杂交（RNA-ISH）评估了整个组织切片中 LINC01187mRNA 的表达模式，这些组织切片代表了 197 例 RCC 病例的队列，包括原发性和转移性肿瘤。
观察指标和统计分析
对每个病例的 FOXI1 和 RHCG IHC 染色以及 LINC01187 RNA-ISH 染色的强度、模式和表达定位进行评估。
结果和局限性
所有原发性和转移性经典 ChRCC 均显示 FOXI1、RHCG 蛋白和 LINC01187 转录本的均匀阳性标记。具有嗜酸细胞特征的未分类 RCC、嗜酸细胞瘤和混合嗜酸细胞瘤，以及除 2 例嗜酸细胞 ChRCC 外的所有病例均呈阳性染色。重要的是，所有其他亚型的转移性和原发性 RCC 均未显示出 FOXI1、RHCG 或 LINC01187 的任何明确染色。在正常肾脏中，FOXI1、RHCG 和 LINC01187 检测到在远端肾单位段，特别是在闰细胞中。发现 2 例具有局灶性 FOXI1 和 LINC01187 表达及高尔基样 RHCG 染色的嗜酸细胞 ChRCC 病例中存在 MTOR 基因突变。
结论
我们展示了一种鉴定和验证 RCC 亚型特异性生物标志物的方法，该方法可帮助确认细胞起源，并可能有助于准确分类和诊断肾肿瘤。
患者总结
FOXI1、RHCG 和 LINC01187 是嫌色细胞肾细胞癌的谱系特异性特征基因。
Zotero 插件