Advancing Precision Oncology in Hereditary Paraganglioma-Pheochromocytoma Syndromes: Integrated Interpretation and Data Sharing of the Germline and Tumor Genomes

Simple Summary: The standard interpretation methods of germline variants in cancer are limited due to overlapping features in constitutional and sporadically derived forms of cancers and the unavailability of key differentiating details in public settings. To address this challenge, we established INT(2)GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes), a multi-institution oncology consortium to advance the integrated application of constitutional and tumor data and share the integrated variant data in a publicly accessible knowledgebase. The aim of our study is to introduce INT(2)GRATE|HPPGL, a platform for the integrated interpretation of hereditary paraganglioma-pheochromocytoma syndromes (HPPGL). We describe the details of the INT(2)GRATE|HPPGL Variant Evidence Framework for succinate dehydrogenase (SDHx) genes using key HPPGL personal and family history, as well as tumor-derived evidence. We applied the INT(2)GRATE|HPPGL Variant Evidence Framework to 8600 variants to programmatically process and share the integrated variant data in ClinVar using a custom-made INT(2)GRATE variant submission pipeline. This novel integrated variant assessment and data sharing in hereditary cancers is essential to help improve the clinical interpretation of genomic variants and advance precision oncology. 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 INT(2)GRATE|HPPGL platform. INT(2)GRATE (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 INT(2)GRATE|HPPGL platform enables automated parsing and integrated assessment of germline, tumor, and genetic findings in hereditary paraganglioma-pheochromocytoma syndromes (HPPGLs). Using INT(2)GRATE|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, KIT and PDGFRA status in gastrointestinal stromal tumors (GISTs), multifocal or extra-adrenal tumors, and metastasis status; and immunohistochemistry staining status for SDHA and SDHB genes. After processing, 8600 variants were submitted programmatically from the INT(2)GRATE|HPPGL platform to ClinVar via a custom-made INT(2)GRATE|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.