birt - hogg - dub综合征肾肿瘤：综合组织病理学、体积和单细胞转录组学分析

IF 25.3 1区医学 Q1 UROLOGY & NEPHROLOGY

European urology Pub Date : 2025-04-18 DOI:10.1016/j.eururo.2025.03.012

Sounak Gupta, Surendra Dasari, Rachel R. Warren, Wei Shen, Rhianna M. Urban, Melissa L. Stanton, Christine M. Lohse, Megan A. Holdren, Megan F. Hoenig, Beth A. Pitel, Stephanie A. Smoley, Stefan W. Nelson, Nate R. Torell, Autumn C. Moon, Leah M. Nelson, Joaquin J. Garcia, Peter C. Lucas, Kevin C. Halling, Benjamin R. Kipp, Stephen A. Boorjian, Bradley C. Leibovich

{"title":"birt - hogg - dub<s:1>综合征肾肿瘤：综合组织病理学、体积和单细胞转录组学分析","authors":"Sounak Gupta, Surendra Dasari, Rachel R. Warren, Wei Shen, Rhianna M. Urban, Melissa L. Stanton, Christine M. Lohse, Megan A. Holdren, Megan F. Hoenig, Beth A. Pitel, Stephanie A. Smoley, Stefan W. Nelson, Nate R. Torell, Autumn C. Moon, Leah M. Nelson, Joaquin J. Garcia, Peter C. Lucas, Kevin C. Halling, Benjamin R. Kipp, Stephen A. Boorjian, Bradley C. Leibovich","doi":"10.1016/j.eururo.2025.03.012","DOIUrl":null,"url":null,"abstract":"<h3>Background and objective</h3>It is unclear whether historically diagnosed “hybrid tumors” in patients with Birt-Hogg-Dubé syndrome (BHD) represent unique tumors or a hybrid between oncocytoma and chromophobe renal cell carcinoma (Ch-RCC), and existing diagnostic criteria are ambiguous. We aimed to understand the spectrum of <em>folliculin</em> gene (<em>FLCN)</em> alterations, outcomes for BHD patients with kidney tumors, and the biology of <em>FLCN</em>-mutated tumors (FMTs) to refine diagnostic algorithms.<h3>Methods</h3>Germline testing for <em>FLCN</em> alterations and outcomes for 20 BHD patients with 84 kidney tumors were evaluated. Renal tumors were profiled for histopathology and analyzed using a combination of next-generation sequencing, bulk/single-cell transcriptomic analysis, and immunohistochemistry (IHC).<h3>Key findings and limitations</h3>Ninety unique germline <em>FLCN</em> variants in 234 unrelated families included rare deletion events (14/234, 6%), including those of the promoter region. Most patients (17/19, 90%) met the National Comprehensive Cancer Network criteria for germline testing. Almost all cases represented indolent FMTs (<em>n</em> = 81), with metastases seen in two (of three) nonconventional renal cell carcinoma patients. FMTs showed a gene expression profile distinct from both oncocytoma and Ch-RCC characterized by four distinct <em>L1CAM</em><sup>–</sup>/<em>FOXI1</em><sup>+</sup> and two <em>L1CAM</em><sup>+</sup>/<em>FOXI1</em><sup>–</sup> cell populations that showed <em>GPNMB</em> overexpression. IHC panels that include L1CAM, SOX9, and GPNMB can be a reliable screen for conventional FMTs. Limitations include the absence of external transcriptomic datasets to avoid batch effects.<h3>Conclusions and clinical implications</h3>Our results highlight the gaps in current clinical germline testing strategies for BHD, which should include promoter deletion events. Multimodal molecular profiling results can be translated into routine clinical practice using IHC biomarkers to improve the diagnosis of BHD and to separate indolent “conventional” FMTs from “nonconventional tumors,” which may be clinically aggressive.","PeriodicalId":12223,"journal":{"name":"European urology","volume":"64 1","pages":""},"PeriodicalIF":25.3000,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Renal Neoplasia in Birt-Hogg-Dubé Syndrome: Integrated Histopathologic, Bulk, and Single-cell Transcriptomic Analysis\",\"authors\":\"Sounak Gupta, Surendra Dasari, Rachel R. Warren, Wei Shen, Rhianna M. Urban, Melissa L. Stanton, Christine M. Lohse, Megan A. Holdren, Megan F. Hoenig, Beth A. Pitel, Stephanie A. Smoley, Stefan W. Nelson, Nate R. Torell, Autumn C. Moon, Leah M. Nelson, Joaquin J. Garcia, Peter C. Lucas, Kevin C. Halling, Benjamin R. Kipp, Stephen A. Boorjian, Bradley C. Leibovich\",\"doi\":\"10.1016/j.eururo.2025.03.012\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<h3>Background and objective</h3>It is unclear whether historically diagnosed “hybrid tumors” in patients with Birt-Hogg-Dubé syndrome (BHD) represent unique tumors or a hybrid between oncocytoma and chromophobe renal cell carcinoma (Ch-RCC), and existing diagnostic criteria are ambiguous. We aimed to understand the spectrum of <em>folliculin</em> gene (<em>FLCN)</em> alterations, outcomes for BHD patients with kidney tumors, and the biology of <em>FLCN</em>-mutated tumors (FMTs) to refine diagnostic algorithms.<h3>Methods</h3>Germline testing for <em>FLCN</em> alterations and outcomes for 20 BHD patients with 84 kidney tumors were evaluated. Renal tumors were profiled for histopathology and analyzed using a combination of next-generation sequencing, bulk/single-cell transcriptomic analysis, and immunohistochemistry (IHC).<h3>Key findings and limitations</h3>Ninety unique germline <em>FLCN</em> variants in 234 unrelated families included rare deletion events (14/234, 6%), including those of the promoter region. Most patients (17/19, 90%) met the National Comprehensive Cancer Network criteria for germline testing. Almost all cases represented indolent FMTs (<em>n</em> = 81), with metastases seen in two (of three) nonconventional renal cell carcinoma patients. FMTs showed a gene expression profile distinct from both oncocytoma and Ch-RCC characterized by four distinct <em>L1CAM</em><sup>–</sup>/<em>FOXI1</em><sup>+</sup> and two <em>L1CAM</em><sup>+</sup>/<em>FOXI1</em><sup>–</sup> cell populations that showed <em>GPNMB</em> overexpression. IHC panels that include L1CAM, SOX9, and GPNMB can be a reliable screen for conventional FMTs. Limitations include the absence of external transcriptomic datasets to avoid batch effects.<h3>Conclusions and clinical implications</h3>Our results highlight the gaps in current clinical germline testing strategies for BHD, which should include promoter deletion events. Multimodal molecular profiling results can be translated into routine clinical practice using IHC biomarkers to improve the diagnosis of BHD and to separate indolent “conventional” FMTs from “nonconventional tumors,” which may be clinically aggressive.\",\"PeriodicalId\":12223,\"journal\":{\"name\":\"European urology\",\"volume\":\"64 1\",\"pages\":\"\"},\"PeriodicalIF\":25.3000,\"publicationDate\":\"2025-04-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European urology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.eururo.2025.03.012\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"UROLOGY & NEPHROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European urology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.eururo.2025.03.012","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"UROLOGY & NEPHROLOGY","Score":null,"Total":0}

引用次数: 0

摘要

背景与目的目前尚不清楚在birt - hogg - dub综合征（BHD）患者中，历史上诊断的“杂交肿瘤”是一种独特的肿瘤，还是嗜细胞瘤和嫌色肾细胞癌（Ch-RCC）之间的杂交肿瘤，现有的诊断标准也不明确。我们的目的是了解卵泡蛋白基因（FLCN）改变的谱，BHD患者合并肾肿瘤的结局，以及FLCN突变肿瘤（FMTs）的生物学，以完善诊断算法。方法对20例BHD患者84例肾肿瘤进行FLCN改变的生殖系检测和预后评估。采用新一代测序、批量/单细胞转录组分析和免疫组织化学（IHC）对肾肿瘤进行组织病理学分析。关键发现和局限性：在234个不相关的家族中，90个独特的种系FLCN变异包括罕见的缺失事件（14/ 234,6 %），包括启动子区域的缺失事件。大多数患者（17/19,90%）符合国家综合癌症网络的生殖系检测标准。几乎所有病例均为惰性fmt (n = 81)，其中2 / 3为非常规肾细胞癌。FMTs的基因表达谱不同于嗜瘤细胞瘤和Ch-RCC，其特征是四个不同的L1CAM - /FOXI1+和两个L1CAM+/FOXI1 -细胞群显示GPNMB过表达。包括L1CAM， SOX9和GPNMB在内的IHC面板可以作为常规fmt的可靠屏幕。限制包括缺乏外部转录组学数据集，以避免批量效应。研究结果强调了目前BHD临床生殖系检测策略的差距，其中应该包括启动子缺失事件。多模态分子谱分析结果可以转化为常规临床实践，使用IHC生物标志物来提高BHD的诊断，并将惰性的“传统”FMTs与可能具有临床侵袭性的“非常规肿瘤”区分开来。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Renal Neoplasia in Birt-Hogg-Dubé Syndrome: Integrated Histopathologic, Bulk, and Single-cell Transcriptomic Analysis

Background and objective

It is unclear whether historically diagnosed “hybrid tumors” in patients with Birt-Hogg-Dubé syndrome (BHD) represent unique tumors or a hybrid between oncocytoma and chromophobe renal cell carcinoma (Ch-RCC), and existing diagnostic criteria are ambiguous. We aimed to understand the spectrum of folliculin gene (FLCN) alterations, outcomes for BHD patients with kidney tumors, and the biology of FLCN-mutated tumors (FMTs) to refine diagnostic algorithms.

Methods

Germline testing for FLCN alterations and outcomes for 20 BHD patients with 84 kidney tumors were evaluated. Renal tumors were profiled for histopathology and analyzed using a combination of next-generation sequencing, bulk/single-cell transcriptomic analysis, and immunohistochemistry (IHC).

Key findings and limitations

Ninety unique germline FLCN variants in 234 unrelated families included rare deletion events (14/234, 6%), including those of the promoter region. Most patients (17/19, 90%) met the National Comprehensive Cancer Network criteria for germline testing. Almost all cases represented indolent FMTs (n = 81), with metastases seen in two (of three) nonconventional renal cell carcinoma patients. FMTs showed a gene expression profile distinct from both oncocytoma and Ch-RCC characterized by four distinct L1CAM^–/FOXI1⁺ and two L1CAM⁺/FOXI1^– cell populations that showed GPNMB overexpression. IHC panels that include L1CAM, SOX9, and GPNMB can be a reliable screen for conventional FMTs. Limitations include the absence of external transcriptomic datasets to avoid batch effects.

Conclusions and clinical implications

Our results highlight the gaps in current clinical germline testing strategies for BHD, which should include promoter deletion events. Multimodal molecular profiling results can be translated into routine clinical practice using IHC biomarkers to improve the diagnosis of BHD and to separate indolent “conventional” FMTs from “nonconventional tumors,” which may be clinically aggressive.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

European urology 医学-泌尿学与肾脏学

CiteScore

43.00

自引率

2.60%

发文量

1753

审稿时长

23 days

期刊介绍： European Urology is a peer-reviewed journal that publishes original articles and reviews on a broad spectrum of urological issues. Covering topics such as oncology, impotence, infertility, pediatrics, lithiasis and endourology, the journal also highlights recent advances in techniques, instrumentation, surgery, and pediatric urology. This comprehensive approach provides readers with an in-depth guide to international developments in urology.