文章：

推进冯·希佩尔-林道综合征临床可操作性研究：来自INT2GRATE肿瘤学联盟的循证框架

Advancing the Landscape of Clinical Actionability in Von Hippel–Lindau Syndrome: An Evidence-Based Framework from the INT2GRATE Oncology Consortium

原文发布日期：27 June 2025

DOI: 10.3390/cancers17132173

类型: Article

开放获取: 是

英文摘要：

Background/Objectives:An accurate evaluation of variant actionability is essential in cancer management. In Von Hippel–Lindau Syndrome (VHL), the interpretation of the germline variants is confounded by the presence of non-syndromic component tumors, such as clear cell renal cell carcinoma (ccRCC), hemangioblastoma, pheochromocytoma, and neuroendocrine tumors. These tumors frequently occur sporadically, without any association with VHL syndrome. The presence of these tumors in a patient with a germlineVHLvariant could lead to inaccurate attribution of these tumors to the germline variant and VHL syndrome. In our previous INT2GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) programs, we demonstrated that integrating tumor-derived and germline evidence offers a comprehensive approach for the accurate assessment of the germline variants in cancer syndromes.Methods/Results:Here, we present a novel INT2GRATE variant evidence framework (VEF) for evaluating the clinical actionability of the germline variants in VHL syndrome, offering an integrated approach that incorporates both constitutional and tumor data. We analyzed 2672 variants in theVHLgene and their associated tumors and clinical evidence to effectively distinguish between constitutional, sporadic, VHL differentials, andVHLallelic genetic conditions. The germline INT2GRATE variants, along with their comprehensive associated evidence, were made accessible in the first open-access INT2GRATE Variant data Portal.Conclusions:This novel and integrated approach to variant assessment and data sharing in hereditary cancer syndromes is essential in the clinical evaluation of genomic variants, advancing precision oncology, and improving patient care.

摘要翻译： 

背景/目的：在癌症管理中，准确评估变异体的临床可操作性至关重要。在希佩尔-林道综合征（VHL）中，种系变异的解读常因非综合征性成分肿瘤的存在而复杂化，例如透明细胞肾细胞癌、血管母细胞瘤、嗜铬细胞瘤和神经内分泌肿瘤。这些肿瘤常为散发性发生，与VHL综合征无明确关联。若患者携带VHL种系变异并出现此类肿瘤，可能导致错误地将肿瘤归因于种系变异及VHL综合征。在我们先前的INT2GRATE（种系与肿瘤基因组整合解读）项目中，我们证实整合肿瘤来源证据与种系证据可为癌症综合征的种系变异评估提供全面方法。 方法/结果：本研究提出一种新型INT2GRATE变异证据框架，用于评估VHL综合征种系变异的临床可操作性。该整合方法同时纳入体质性数据与肿瘤数据。通过分析VHL基因的2672个变异及其相关肿瘤与临床证据，我们有效区分了体质性、散发性、VHL鉴别诊断及VHL等位基因遗传状态。所有INT2GRATE种系变异及其完整关联证据均已收录于首个开放获取的INT2GRATE变异数据门户平台。 结论：这种整合变异评估与数据共享的新方法对遗传性癌症综合征的基因组变异临床评估、推进精准肿瘤学发展及改善患者诊疗具有重要意义。

原文链接：

Advancing the Landscape of Clinical Actionability in Von Hippel–Lindau Syndrome: An Evidence-Based Framework from the INT2GRATE Oncology Consortium