Rana Huma Q, Koeller Diane R, Walker McKenzie, Unal Busra, Levine Alison Schwartz, Chittenden Anu, Isidro Raymond A, Hayes Connor P, Manam Monica D, Buehler Ryan M, Manning Danielle K, Barletta Justine A, Hornick Jason L, Garber Judy E, Ghazani Arezou A
Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Cancers (Basel). 2024 Feb 26;16(5):947. doi: 10.3390/cancers16050947.
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 INTGRATE|HPPGL platform. INTGRATE (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 INTGRATE|HPPGL platform enables automated parsing and integrated assessment of germline, tumor, and genetic findings in hereditary paraganglioma-pheochromocytoma syndromes (HPPGLs). Using INTGRATE|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, and status in gastrointestinal stromal tumors (GISTs), multifocal or extra-adrenal tumors, and metastasis status; and immunohistochemistry staining status for and genes. After processing, 8600 variants were submitted programmatically from the INTGRATE|HPPGL platform to ClinVar via a custom-made INTGRATE|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.
遗传性癌症易感性基因变异评估的标准方法因缺乏关键支持证据而受到限制。在癌症中，来自肿瘤的信息可作为描绘肿瘤行为以及种系变异在肿瘤进展中作用的有用来源。我们之前已经证明了整合肿瘤和种系研究结果以全面评估遗传性癌症综合征中种系变异的价值。在此基础上，我们展示了INTGRATE|HPPGL平台的开发与应用。INTGRATE（种系和肿瘤基因组的综合解释）是一个多机构肿瘤学联盟，旨在推进体质和肿瘤数据的综合应用，并在可公开访问的知识库中共享综合变异信息。INTGRATE|HPPGL平台能够对遗传性副神经节瘤 - 嗜铬细胞瘤综合征（HPPGL）中的种系、肿瘤和基因研究结果进行自动解析和综合评估。使用INTGRATE|HPPGL，我们分析了琥珀酸脱氢酶（SDHx）基因中的8600个变异及其相关临床证据。综合证据包括SDHx基因中的种系变异；临床遗传学证据：HPPGL相关肿瘤的个人和家族病史；肿瘤衍生证据：SDHx等位基因的体细胞失活，以及在胃肠道间质瘤（GIST）、多灶性或肾上腺外肿瘤中的状态和转移状态；以及 和 基因的免疫组化染色状态。处理后，8600个变异通过定制的INTGRATE|HPPGL变异提交模式和应用程序编程接口（API）从INTGRATE|HPPGL平台以编程方式提交至ClinVar。这种遗传性癌症中新型的综合变异评估和数据共享旨在改善基因组变异的临床评估并推进精准肿瘤学发展。
Zotero 插件