Koeller Diane R, Walker McKenzie, Unal Busra, Chittenden Anu, Levine Alison Schwartz, Hayes Connor P, Oramasionwu Paul C, Manam Monica D, Buehler Ryan M, Gomy Israel, Silva Wilson Araujo, Lerner-Ellis Jordan, Casalino Selina, Mahajan Radhika, Watkins Nicholas, Agaoglu Nihat Bugra, Manning Danielle K, Barletta Justine A, Hornick Jason L, Lindeman Neal I, Sholl Lynette M, Rana Huma Q, Garber Judy E, Ghazani Arezou A
Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
Cancers (Basel). 2025 Jun 27;17(13):2173. doi: 10.3390/cancers17132173.
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 germline variant could lead to inaccurate attribution of these tumors to the germline variant and VHL syndrome. In our previous INTGRATE (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. Here, we present a novel INTGRATE 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 the gene and their associated tumors and clinical evidence to effectively distinguish between constitutional, sporadic, VHL differentials, and allelic genetic conditions. The germline INTGRATE variants, along with their comprehensive associated evidence, were made accessible in the first open-access INTGRATE Variant data Portal. 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.
准确评估变异的可操作性在癌症管理中至关重要。在Von Hippel-Lindau综合征（VHL）中，种系变异的解释因存在非综合征性组分肿瘤而变得复杂，如透明细胞肾细胞癌（ccRCC）、成血管细胞瘤、嗜铬细胞瘤和神经内分泌肿瘤。这些肿瘤经常散发性发生，与VHL综合征无任何关联。种系变异患者中这些肿瘤的存在可能导致将这些肿瘤错误归因于种系变异和VHL综合征。在我们之前的INTGRATE（种系和肿瘤基因组的综合解释）项目中，我们证明整合肿瘤衍生证据和种系证据为准确评估癌症综合征中的种系变异提供了一种全面的方法。在此，我们提出了一种新颖的INTGRATE变异证据框架（VEF），用于评估VHL综合征中种系变异的临床可操作性，提供一种整合了体质数据和肿瘤数据的综合方法。我们分析了该基因中的2672个变异及其相关肿瘤和临床证据，以有效区分体质性、散发性、VHL鉴别诊断和等位基因遗传状况。种系INTGRATE变异及其全面的相关证据可在首个开放获取的INTGRATE变异数据门户中获取。这种用于遗传性癌症综合征变异评估和数据共享的新颖且综合的方法在基因组变异的临床评估、推进精准肿瘤学以及改善患者护理方面至关重要。
