Standard methods of variant assessment in hereditary cancer susceptibility genes are limited by the lack of availability of key supporting evidence. In cancer, information derived from tumors can serve as a useful source in delineating the tumor behavior and the role of germline variants in tumor progression. We have previously demonstrated the value of integrating tumor and germline findings to comprehensively assess germline variants in hereditary cancer syndromes. Building on this work, herein, we present the development and application of the INT2GRATE|HPPGL platform. INT2GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) is a multi-institution oncology consortium that aims to advance the integrated application of constitutional and tumor data and share the integrated variant information in publicly accessible repositories. The INT2GRATE|HPPGL platform enables automated parsing and integrated assessment of germline, tumor, and genetic findings in hereditary paraganglioma–pheochromocytoma syndromes (HPPGLs). Using INT2GRATE|HPPGL, we analyzed 8600 variants in succinate dehydrogenase (SDHx) genes and their associated clinical evidence. The integrated evidence includes germline variants in SDHx genes; clinical genetics evidence: personal and family history of HPPGL-related tumors; tumor-derived evidence: somatic inactivation of SDHx alleles,KITandPDGFRAstatus in gastrointestinal stromal tumors (GISTs), multifocal or extra-adrenal tumors, and metastasis status; and immunohistochemistry staining status forSDHAandSDHBgenes. After processing, 8600 variants were submitted programmatically from the INT2GRATE|HPPGL platform to ClinVar via a custom-made INT2GRATE|HPPGL variant submission schema and an application programming interface (API). This novel integrated variant assessment and data sharing in hereditary cancers aims to improve the clinical assessment of genomic variants and advance precision oncology.
遗传性癌症易感基因的变异评估标准方法因缺乏关键支持证据而受限。在癌症研究中，源自肿瘤的信息可作为阐明肿瘤行为及种系变异在肿瘤进展中作用的重要依据。我们先前已证明整合肿瘤与种系检测结果对全面评估遗传性癌症综合征种系变异的价值。基于此，本文介绍INT2GRATE|HPPGL平台的开发与应用。INT2GRATE（种系与肿瘤基因组整合解读联盟）是由多机构组成的肿瘤学联盟，致力于推进体质性与肿瘤数据的整合应用，并通过公开数据库共享整合变异信息。INT2GRATE|HPPGL平台实现了对遗传性副神经节瘤-嗜铬细胞瘤综合征（HPPGLs）中种系、肿瘤及遗传学发现的自动化解析与整合评估。利用该平台，我们分析了琥珀酸脱氢酶（SDHx）基因的8600个变异及其相关临床证据。整合证据包括：SDHx基因种系变异；临床遗传学证据：HPPGL相关肿瘤的个人史与家族史；肿瘤来源证据：SDHx等位基因体细胞失活、胃肠道间质瘤（GISTs）中KIT与PDGFRA状态、多灶性或肾上腺外肿瘤及转移状态；以及SDHA和SDHB基因免疫组化染色状态。经处理后，8600个变异通过定制化的INT2GRATE|HPPGL变异提交模式与应用编程接口（API），从平台自动提交至ClinVar数据库。这种创新的遗传性癌症整合变异评估与数据共享模式，旨在提升基因组变异的临床评估水平，推动精准肿瘤学发展。
肿瘤(癌症)患者之家