An integrated somatic and germline approach to aid interpretation of germline variants of uncertain significance in cancer susceptibility genes

Schwartz, Alison; Manning, Danielle K.; Koeller, Diane R.; Chittenden, Anu; Isidro, Raymond A; Hayes, Connor P; Manam, Monica; Dwan, Meaghan; Barletta, Justine A.; Sholl, Lynette M.; Yurgelun, Matthew B.; Rana, Huma Q.; Garber, Judy E.

doi:10.3389/fonc.2022.942741

Cited by 6 publications

(5 citation statements)

References 66 publications

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“…Harnessing relevant tumor information can serve as strong evidence to help delineate the function of germline variants in cancer susceptibility genes. We have previously demonstrated the utility of tumor-derived data in the reassessment of the pathogenicity of germline variants in patients with non-syndromic phenotypes [ 5 , 6 , 7 , 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…Tumor testing was performed by the OncoPanel test at the Center for Advanced Molecular Diagnostics (CAMD) laboratory in the Pathology Department at Brigham and Women’s Hospital (BWH, Boston, MA, USA) as part of a routine clinical test and as previously described [ 8 ].…”

Section: Methodsmentioning

confidence: 99%

“…For cases stained at BWH, IHC for SDHA and/or SDHB proteins was performed as previously described [ 8 ]. Briefly, slides with formalin-fixed, paraffin-embedded tissue sections were deparaffinized, rehydrated, subjected to antigen retrieval (pressure cooker; pH, 6.1; citrate buffer; Target Retrieval Solution, DAKO, Santa Clara, CA, USA), and incubated with the primary antibodies targeting SDHA (1:800, clone 2E3; ab14715, Abcam, Chuo City, Tokyo) or SDHB (1:300, clone 21A11; ab14714, Abcam, Chuo City, Tokyo).…”

Section: Methodsmentioning

confidence: 99%

“…We have previously demonstrated the utility of tumor-derived and clinical genetic information in elucidating the clinical relevance of germline variants in selected cancers [ 5 , 6 , 7 , 8 ]. INT 2 GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) is a multi-institution oncology consortium.…”

Section: Introductionmentioning

confidence: 99%

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

Rana,

Koeller,

Walker

et al. 2024

Cancers

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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, 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 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.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Rana,

Koeller,

Walker

et al. 2024

Cancers

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“…The segregation of germline and somatic variant databases further perpetuates the lack of integration of constitutional and tumor-derived information. We have previously demonstrated the value of the integrated germline and somatic framework in assessing the pathogenicity of germline variants in several cancer syndromes (7)(8)(9)(10)(11)(12), and the utility of this integrated approach in the assessment of germline variants of uncertain significance (VUS) in cancer susceptibility genes (7). There is currently a need for objective assessment of VUS in high-risk individuals where germline variants might be actionable, or in other genetic settings where the identification of MMR variants might help preventative approaches.…”

Section: Introductionmentioning

confidence: 99%

Development and evaluation of INT2GRATE: a platform for comprehensive assessment of the role of germline variants informed by tumor signature profile in Lynch syndrome

Isidro,

Chittenden,

Walker

et al. 2024

Front. Oncol.

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The presence of variants of uncertain significance (VUS) in DNA mismatch repair (MMR) genes leads to uncertainty in the clinical management of patients being evaluated for Lynch syndrome (LS). Currently, there is no platform to systematically use tumor-derived evidence alongside germline data for the assessment of VUS in relation to LS. We developed INT2GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) to leverage information from the tumor genome to inform the potential role of constitutional VUS in MMR genes. INT2GRATE platform has two components: a comprehensive evidence-based decision tree that integrates well-established clinico-genomic data from both the tumor and constitutional genomes to help inform the potential relevance of germline VUS in LS; and a web-based user interface (UI). With the INT2GRATE decision tree operating in the backend, INT2GRATE UI enables the front-end collection of comprehensive clinical genetics and tumor-derived evidence for each VUS to facilitate INT2GRATE assessment and data sharing in the publicly accessible ClinVar database. The performance of the INT2GRATE decision tree was assessed by qualitative retrospective analysis of genomic data from 5057 cancer patients with MMR alterations which included 52 positive control cases. Of 52 positive control cases with LS and pathogenic MMR alterations, 23 had all the testing parameters for the evaluation by INT2GRATE. All these variants were correctly categorized as INT2GRATE POSITIVE. The stringent INT2GRATE decision tree flagged 29 of positive cases by identifying the absence or unusual presentation of specific evidence, highlighting the conservative INT2GRATE logic in favor of a higher degree of confidence in the results. The remaining 99% of cases were correctly categorized as INCONCLUSIVE due to the absence of LS criteria and ≥1 tumor parameters. INT2GRATE is an effective platform for clinical and genetics professionals to collect and assess clinical genetics and complimentary tumor-derived information for each germline VUS in suspected LS patients. Furthermore, INT2GRATE enables the collation of integrated tumor-derived evidence relevant to germline VUS in LS, and sharing them with a large community, a practice that is needed in precision oncology.

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ClinVar: updates to support classifications of both germline and somatic variants

Landrum,

Chitipiralla,

Kaur

et al. 2024

Nucleic Acids Research

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ClinVar (www.ncbi.nlm.nih.gov/clinvar/) is a free, public database of human genetic variants and their relationships to disease, with >3 million variants submitted by >2800 organizations across the world. The database was recently updated to have three types of classifications: germline, oncogenicity and clinical impact for somatic variants. As for germline variants, classifications for somatic variants can be submitted in batches in a file submission or through the submission API; variants can also be submitted and updated one at a time in online submission forms. The ClinVar XML files were redesigned to allow multiple classification types. Both old and new formats of the XML are supported through the end of 2024. Data for somatic classifications were also added to the ClinVar VCF files and to several tab-delimited files. The ClinVar VCV pages were updated to display the three types of classifications, both as it was submitted and as it was aggregated by ClinVar. Clinical testing laboratories and others in the cancer community are invited to share their classifications of somatic variant classifications through ClinVar to provide transparency in genomic testing and improve patient care.

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An integrated somatic and germline approach to aid interpretation of germline variants of uncertain significance in cancer susceptibility genes

Cited by 6 publications

References 66 publications

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

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

Development and evaluation of INT2GRATE: a platform for comprehensive assessment of the role of germline variants informed by tumor signature profile in Lynch syndrome

ClinVar: updates to support classifications of both germline and somatic variants

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