Advancing Precision Oncology in Hereditary Paraganglioma-Pheochromocytoma Syndromes: Integrated Interpretation and Data Sharing of the Germline and Tumor Genomes
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 pr...
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/16/5/947 |
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| author | Huma Q. Rana Diane R. Koeller McKenzie Walker Busra Unal Alison Schwartz Levine Anu Chittenden Raymond A. Isidro Connor P. Hayes Monica D. Manam Ryan M. Buehler Danielle K. Manning Justine A. Barletta Jason L. Hornick Judy E. Garber Arezou A. Ghazani INT<sup>2</sup>GRATE Oncology Consortium |
| author_facet | Huma Q. Rana Diane R. Koeller McKenzie Walker Busra Unal Alison Schwartz Levine Anu Chittenden Raymond A. Isidro Connor P. Hayes Monica D. Manam Ryan M. Buehler Danielle K. Manning Justine A. Barletta Jason L. Hornick Judy E. Garber Arezou A. Ghazani INT<sup>2</sup>GRATE Oncology Consortium |
| author_sort | Huma Q. Rana |
| collection | DOAJ |
| description | 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<sup>2</sup>GRATE|HPPGL platform. INT<sup>2</sup>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<sup>2</sup>GRATE|HPPGL platform enables automated parsing and integrated assessment of germline, tumor, and genetic findings in hereditary paraganglioma–pheochromocytoma syndromes (HPPGLs). Using INT<sup>2</sup>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, <i>KIT</i> and <i>PDGFRA</i> status in gastrointestinal stromal tumors (GISTs), multifocal or extra-adrenal tumors, and metastasis status; and immunohistochemistry staining status for <i>SDHA</i> and <i>SDHB</i> genes. After processing, 8600 variants were submitted programmatically from the INT<sup>2</sup>GRATE|HPPGL platform to ClinVar via a custom-made INT<sup>2</sup>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. |
| first_indexed | 2024-04-25T00:33:33Z |
| format | Article |
| id | doaj.art-9ac0d0ed287c4142a6b82ba22a827c2d |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-04-25T00:33:33Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-9ac0d0ed287c4142a6b82ba22a827c2d2024-03-12T16:40:56ZengMDPI AGCancers2072-66942024-02-0116594710.3390/cancers16050947Advancing Precision Oncology in Hereditary Paraganglioma-Pheochromocytoma Syndromes: Integrated Interpretation and Data Sharing of the Germline and Tumor GenomesHuma Q. Rana0Diane R. Koeller1McKenzie Walker2Busra Unal3Alison Schwartz Levine4Anu Chittenden5Raymond A. Isidro6Connor P. Hayes7Monica D. Manam8Ryan M. Buehler9Danielle K. Manning10Justine A. Barletta11Jason L. Hornick12Judy E. Garber13Arezou A. Ghazani14INT<sup>2</sup>GRATE Oncology ConsortiumDivision of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA 02215, USADivision of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA 02215, USADivision of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USADivision of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USADivision of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA 02215, USADivision of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USADivision of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USADepartment of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USADivision of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USAHarvard Medical School, Boston, MA 02115, USAHarvard Medical School, Boston, MA 02115, USADivision of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA 02215, USAHarvard Medical School, Boston, MA 02115, USAStandard 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<sup>2</sup>GRATE|HPPGL platform. INT<sup>2</sup>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<sup>2</sup>GRATE|HPPGL platform enables automated parsing and integrated assessment of germline, tumor, and genetic findings in hereditary paraganglioma–pheochromocytoma syndromes (HPPGLs). Using INT<sup>2</sup>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, <i>KIT</i> and <i>PDGFRA</i> status in gastrointestinal stromal tumors (GISTs), multifocal or extra-adrenal tumors, and metastasis status; and immunohistochemistry staining status for <i>SDHA</i> and <i>SDHB</i> genes. After processing, 8600 variants were submitted programmatically from the INT<sup>2</sup>GRATE|HPPGL platform to ClinVar via a custom-made INT<sup>2</sup>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.https://www.mdpi.com/2072-6694/16/5/947INT<sup>2</sup>GRATE Oncology Consortiumsomatic and germline integrationINT<sup>2</sup>GRATEtumor signature profilegermline VUShereditary paraganglioma–pheochromocytoma syndromes (HPPGLs) |
| spellingShingle | Huma Q. Rana Diane R. Koeller McKenzie Walker Busra Unal Alison Schwartz Levine Anu Chittenden Raymond A. Isidro Connor P. Hayes Monica D. Manam Ryan M. Buehler Danielle K. Manning Justine A. Barletta Jason L. Hornick Judy E. Garber Arezou A. Ghazani INT<sup>2</sup>GRATE Oncology Consortium Advancing Precision Oncology in Hereditary Paraganglioma-Pheochromocytoma Syndromes: Integrated Interpretation and Data Sharing of the Germline and Tumor Genomes Cancers INT<sup>2</sup>GRATE Oncology Consortium somatic and germline integration INT<sup>2</sup>GRATE tumor signature profile germline VUS hereditary paraganglioma–pheochromocytoma syndromes (HPPGLs) |
| title | Advancing Precision Oncology in Hereditary Paraganglioma-Pheochromocytoma Syndromes: Integrated Interpretation and Data Sharing of the Germline and Tumor Genomes |
| title_full | Advancing Precision Oncology in Hereditary Paraganglioma-Pheochromocytoma Syndromes: Integrated Interpretation and Data Sharing of the Germline and Tumor Genomes |
| title_fullStr | Advancing Precision Oncology in Hereditary Paraganglioma-Pheochromocytoma Syndromes: Integrated Interpretation and Data Sharing of the Germline and Tumor Genomes |
| title_full_unstemmed | Advancing Precision Oncology in Hereditary Paraganglioma-Pheochromocytoma Syndromes: Integrated Interpretation and Data Sharing of the Germline and Tumor Genomes |
| title_short | Advancing Precision Oncology in Hereditary Paraganglioma-Pheochromocytoma Syndromes: Integrated Interpretation and Data Sharing of the Germline and Tumor Genomes |
| title_sort | advancing precision oncology in hereditary paraganglioma pheochromocytoma syndromes integrated interpretation and data sharing of the germline and tumor genomes |
| topic | INT<sup>2</sup>GRATE Oncology Consortium somatic and germline integration INT<sup>2</sup>GRATE tumor signature profile germline VUS hereditary paraganglioma–pheochromocytoma syndromes (HPPGLs) |
| url | https://www.mdpi.com/2072-6694/16/5/947 |
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