Raca, Gordana

Abstract The comprehensive evaluation of somatic variants in cancer requires consensus interpretation of their potential clinical significance (diagnosis, prognosis, and treatment response) and oncogenicity. To aid precision medicine through public interpretations, a multifaceted collaborative effort is required to bring together a community, structured guidance, and a public platform. The over 200 multi-disciplinary experts in the Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group (CDWG) provide a community that develops data curation guidelines and standards and curates evidence to determine the clinical significance and oncogenicity of somatic alterations in cancer. The Somatic CDWG established the Pediatric Cancer, Hematological Cancer, and Solid Tumor Taskforces to facilitate membership growth and targeted curation projects. Within these Taskforces, Somatic Cancer Variant Curation Expert Panels (SC-VCEPs) are developed through a 4-step approval process adapted from ClinGen germline VCEP procedures. Five SC-VCEPs (NTRK-fusions, FGFR variants, FLT3 variants, Histone H3 variants, and BCR::ABL1-like B-ALL alterations) are working through the approval process and one (Established Significance) is in the planning stage. SC-VCEPs tailor AMP/ASCO/CAP [PMID:27993330] and ClinGen/CGC/VICC Oncogenicity [PMID:35101336] guidelines, or create new classification guidance to aid granular assessment of their genomic alterations of interest. The Clinical Interpretations of Variants in Cancer (CIViC) knowledgebase provides the public platform for the Taskforces and SC-VCEPs to display their high-quality somatic cancer variant interpretations. These groups curate evidence from published literature and create Assertions summarizing evidence collected. These Assertions are further disseminated through other resources like ClinVar and the Variant Interpretation for Cancer Consortium (VICC) MetaKB. CIViC supports the application of AMP/ASCO/CAP tiering and levels for clinical significance Assertions. CIViC recently created Oncogenic Assertions, which supports the application of ClinGen/CGC/VICC codes. Three SC-VCEPs (FGFR, FLT3, and Histone H3) are tailoring the ClinGen/CGC/VICC Oncogenicity guidelines to their specific genes and CIViC will enable their ClinGen-approved, modified codes to be applied directly to their Oncogenic Assertions. Also, two SC-VCEPs (NTRK and BCR::ABL1-like) are developing fusion specific oncogenicity classification guidelines, which will be applied to their fusion specific CIViC Oncogenic Assertions. ClinGen Somatic groups have generated 695 CIViC Evidence Items and 33 Assertions from over 400 published papers. These numbers will continue to grow along with the development of more SC-VCEPs. ClinGen Somatic and CIViC foster collaboration, innovation, and most importantly the advancement of precision medicine. Citation Format: Jason Saliba, Arpad Danos, Kilannin Krysiak, Adam Coffman, Susanna Kiwala, Joshua McMichael, Cameron J. Grisdale, Ian King, Shamini Selvarajah, Xinjie Xu, Rashmi Kanagal-Shamanna, Laveniya Satgunaseelan, David Meredith, Mark Evans, Charles G. Mullighan, Yassmine Akkari, Gordana Raca, Angshumoy Roy, Alex H. Wagner, Ramaswamy Govindan, Obi L. Griffith, Malachi Griffith, on behalf of the ClinGen Somatic Clinical Domain Working Group. ClinGen Somatic and CIViC collaborate to comprehensively evaluate somatic variants in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6569.

Abstract CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC’s functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing >3200 variants in >470 genes from >3100 publications.

Abstract Interpretation of the clinical significance of somatic gene variants in cancer remains a major challenge in cancer diagnosis, prognosis and treatment response prediction. We will report on progress and plans of the Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group (CDWG). The CDWG membership consists of over 150 multi-disciplinary experts in cancer biology, oncology, pathology, genetics, genomics and informatics. The mission of the ClinGen Somatic Cancer CDWG is to facilitate the development of data curation guidelines and standards to determine the clinical significance of somatic alterations in cancer, thereby enhancing the usability, dissemination and implementation of cancer somatic changes in the ClinGen resource and other knowledgebases including CIViC, ClinVar, and the Variant Interpretation for Cancer Consortium (VICC) MetaKB. Our goal is to create high-quality assertions of the clinical significance of specific somatic variants in cancer by leveraging the CIViC curation interface, adapting the germline procedures of ClinGen to somatic variant interpretation, and implementing the interoperability standards of the Global Alliance for Genomics and Health (GA4GH). The ClinGen Somatic effort is overseen by the Somatic CDWG and reports progress to the overall ClinGen consortium. There are Somatic Cancer subdomains focused on particular clinically important domains of cancer variant interpretation including three Task Forces (covering Pediatric Cancer, Hematologic Cancer, and Solid Tumors) and a growing number of Somatic Cancer Variant Curation Expert Panels (SC-VCEPs). To improve quality and consistency of clinical interpretations, each candidate somatic cancer VCEP must complete a four step approval process adapted from ClinGen’s work in Germline disease domains. The Somatic CDWG works to ensure that each group is aware of available training materials and detailed standard operating procedures. Each SC-VCEP also coordinates with the ClinGen Cancer Variant Interpretation Committee (CVI) whose goal is to support development of granular specifications for the AMP/ASCO/CAP guidelines for somatic variant interpretation. New SC-VCEPs are anticipated to focus on specific clinically relevant genes, pathways, disease entities, variant classes or treatment modalities. Currently, three SC-VCEPs have begun to work through the four step process (focused on FGFR mutations, NTRK fusions, and FLT3 mutations respectively), and two more SC-VCEPs are in the planning stage (Histone H3 and Ph-like ALL). To date, ClinGen Somatic groups have contributed 619 evidence lines into CIViC from 353 published papers and 21 assertions of clinical significance. Input from the AACR community is critical for the establishment of new SC-VCEPs that address areas of variant interpretation with the greatest need. Citation Format: Jason Saliba, Gordana Raca, Angshumoy Roy, Ian King, Shamini Selvarajah, Xinjie Xu, Rashmi Kanagal-Shamanna, Laveniya Satgunaseelan, David Meredith, Mark Evans, Alanna Church, Panieh Terraf, Yassmine Akkari, Heather E. Williams, Wan-Hsin Lin, Chimene Kesserwan, Deborah I. Ritter, Kilannin Krysiak, Arpad Danos, Alex Wagner, Marilyn M. Li, Dmitriy Sonkin, Jonathan S. Berg, Sharon E. Plon, Heidi L. Rehm, Shashikant Kulkarni, Ramaswamy Govindan, Obi L. Griffith, Malachi Griffith, on behalf of the ClinGen Somatic CDWG. The Clinical Genome Resource (ClinGen) somatic cancer clinical domain working group [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1192.

Abstract Despite the well-established role of recurrent gene fusions as oncogenic drivers, current practices for characterizing and interpreting gene fusion events in clinical testing and in biomedical literature are inconsistent. From the conceptual definition of gene fusions to the salient elements that characterize these alterations, a lack of community-driven standards for the curation of gene fusions has resulted in a disparate landscape of fusion representations and supporting tools. Consequently, the evidence-based clinical evaluation of gene fusions requires extensive expert review for accurate interpretation of observed gene fusions with respect to putative evidence from biomedical literature. Furthermore, the lack of these standards inhibits the interoperability of tools, resources, and pipelines - impeding data sharing and downstream utility.To address these challenges, a cross-consortia initiative between the Variant Interpretation for Cancer Consortium and ClinGen was formed to develop a standard operating procedure (SOP) for the curation of gene fusions. The SOP is under development by an international and diverse set of experts in the representation, detection, and clinical interpretation of gene fusions. Participating stakeholders across academic, government, and industry sectors showcased challenges and solutions, and participated in community surveys and discussions to define and develop the SOP for this diverse class of alterations.An initial result of this effort was the precise molecular definition of genomic events and features constituting gene fusions. We distinguish these from similar but distinct classes of structural alterations through clinically-relevant examples. Next, we discuss our findings on community practices around the description and evaluation of gene fusions. We provide our recommendations for characterization and representation of gene fusions from these practices, and compare these recommendations to existing variant representation standards and formats (e.g. HGVS variant nomenclature). We also discuss the concurrent application of formats for standardized human- and machine-readable representations of gene fusion events.We conclude with discussion of the salient elements to enable rapid, scalable, and consistent evaluation of fusions curated from the biomedical literature. Recommendations are provided for the standardized capture of these elements to enable both intuitive and precise characterization of this diverse class of alterations in clinical reporting and literature. In summary, we provide a clinical-practice driven framework and nomenclature for gene fusions, including recommendations for human readability, computational precision, and data integrity within the SOP. This work is a substantial advancement towards standardized communication, investigation, and sharing of gene fusion data across clinical and research domains and specialties. Citation Format: Alex H. Wagner, Ioannis S. Vlachos, Dmitriy Sonkin, Panieh Terraf, Chimene Kesserwan, Andrea Sboner, Thomas Coard, Christian Reich, Deborah I. Ritter, Peter Horak, Ying S. Zou, Anna Tanska, Aaron M. Berlin, Anna Lu, Daniel Cameron, Heather E. Williams, Wan-Hsin Lin, Gokce Toruner, Arpad Danos, Jason Saliba, Huiling Xu, Xinjie Xu, Georgina Ryland, Michele Ceccarelli, Liying Zhang, Sarah Rapisardo, Catherine Rehder, Xuelu Liu, Aparna Pallavajjala, Nicole Park, Laveniya Satgunaseelan, Kristy Lee, Jie Liu, Obi Griffith, Robert R. Freimuth, Albrecht Stenzinger, Linda B. Baughn, Michael Baudis, Jennifer Lee, Marilyn Li, Angshumoy Roy, Gordana Raca. A standard operating procedure for the curation of gene fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 449.

Abstract Somatic variants in cancer-relevant genes are interpreted from multiple partially overlapping perspectives. When considered in discovery and translational research endeavors, it is important to determine if a particular variant observed in a gene of interest is oncogenic/pathogenic or not, as such knowledge provides the foundation on which targeted cancer treatment research is based. In contrast, clinical applications are dominated by diagnostic, prognostic, or therapeutic interpretations which in part also depends on underlying variant oncogenicity/pathogenicity. The Association for Molecular Pathology, the American Society of Clinical Oncology, and the College of American Pathologists (AMP/ASCO/CAP) have published structured somatic variant clinical interpretation guidelines which specifically address diagnostic, prognostic, and therapeutic implications. These guidelines have been well-received by the oncology community. Many variant knowledgebases, clinical laboratories/centers have adopted or are in the process of adopting these guidelines. The AMP/ASCO/CAP guidelines also describe different data types which are used to determine oncogenicity/pathogenicity of a variant, such as: population frequency, functional data, computational predictions, segregation, and somatic frequency. A second collaborative effort created the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets to provide a harmonized vocabulary that provides an evidence-based ranking system of molecular targets that supports their value as clinical targets. However, neither of these clinical guideline systems provide systematic and comprehensive procedures for aggregating population frequency, functional data, computational predictions, segregation, and somatic frequency to consistently interpret variant oncogenicity/pathogenicity, as has been published in the ACMG/AMP guidelines for interpretation of pathogenicity of germline variants. In order to address this unmet need for somatic variant oncogenicity/pathogenicity interpretation procedures, the Variant Interpretation for Cancer Consortium (VICC, a GA4GH driver project) Knowledge Curation and Interpretation Standards (KCIS) working group (WG) has developed a Standard Operating Procedure (SOP) with contributions from members of ClinGen Somatic Clinical Domain WG, and ClinGen Somatic/Germline variant curation WG using an approach similar to the ACMG/AMP germline pathogenicity guidelines to categorize evidence of oncogenicity/pathogenicity as very strong, strong, moderate or supporting. This SOP enables consistent and comprehensive assessment of oncogenicity/pathogenicity of somatic variants and latest version of an SOP can be found at https://cancervariants.org/wg/kcis/. Citation Format: Peter Horak, Malachi Griffith, Arpad Danos, Beth A. Pitel, Subha Madhavan, Xuelu Liu, Jennifer Lee, Gordana Raca, Shirley Li, Alex H. Wagner, Shashikant Kulkarni, Obi L. Griffith, Debyani Chakravarty, Dmitriy Sonkin. A standard operating procedure for the interpretation of oncogenicity/pathogenicity of somatic mutations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5707.

Abstract Comprehensive interpretation of a patient's cancer genome is a cross-disciplinary process requiring the expertise of oncologists, molecular pathologists, genetic counselors, genomic scientists, and bioinformaticians. The Variant Interpretation for Cancer Consortium (VICC) has created a non-clinical forum for the variant interpretation process by connecting experts from multiple academic institutions and industry to create a Virtual Molecular Tumor Board (VMTB). During VICC-VMTB sessions, experts retrospectively discuss de-identified, challenging patient cases in the context of genomic interpretation guidelines to evaluate a patient's profile across several distinct components: genomic variants; disease context; therapeutic history; family history; demographic information; genomic assay information; and variant allele frequency. These components are processed through the prism of publically available knowledge and expertise of VMTB members, resulting in a broad spectrum of clinically relevant assertions about the patient's disease that may be of prognostic, diagnostic, or predictive relevance. Through these evaluations, the VICC-VMTB primarily works as a means of illuminating challenges in genomic interpretation and advancing the objectives of domain-specific VICC working groups. Examples of challenges that have been highlighted by the VICC-VMTB forum include: 1) inconsistent disease and therapy ontologies across resources are being addressed by Disease Harmonization & Drug Harmonization working groups, respectively; 2) use of machine-learning and natural language processing into clinical-grade variant interpretation are being addressed by the AI-Assisted Curation working group; 3) aggregation and harmonization of knowledgebase data into a centralized resource is being addressed by the Data Licensing and Variant Harmonization working groups; 4) inefficiencies in knowledgebase search functions are being addressed by the Search working group; 5) determination of accurate prediction of biological consequences of rare variants is being addressed by the In Silico Interpretation working group; and 6) standardization of genomic variant curation is being addressed by the Knowledge Curation and Interpretation Standards working group. These VICC working groups provide dedicated expert assemblies intended to specifically tackle these challenges, further increasing the breadth for which genomic information can be made useful in cancer variant interpretation. The VICC-VMTB has been a pertinent link between cancer genomes and clinical interpretation. We are confident VICC-VMTB will continue to be a gateway of acceleration and progress needed in the field of cancer interpretation to provide accurate and efficient answers for our patients in the future. Citation Format: Beth A. Pitel, Shruti Rao, Catherine Del Vecchio Fitz, Subha Madhavan, Rodrigo Dientsmann, Peter Horak, Ian King, Susan M. Mockus, Gordana Raca, Damian T. Rieke, Peter Rogan, Dmitriy Sonkin, David Tamborero, Ioannis S. Vlachos, Brian Walsh, Jeremy L. Warner, Malachi Griffith, Obi L. Griffith, Debyani Chakravarty, Alex H. Wagner. The Virtual Molecular Tumor Board of the Variant Interpretation for Cancer Consortium: A systematic gateway connecting cancer genome interpretation and progress in genomic knowledgebases in cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3222.

Abstract The Clinical Genome (ClinGen) Resource is a US National Human Genome Research Institute (NHGRI)-funded program dedicated to building an expert curated and freely available central resource that defines the clinical relevance of genes and variants for use in precision medicine. Teams of experts in various clinical domains come together as working groups within ClinGen to facilitate the interpretation, annotation and utilization of genes-variants for clinical application. Somatic Cancer is one such ClinGen Clinical Domain Working Group (CDWG) that consists of over 90 members worldwide, including clinicians, clinical laboratory diagnosticians, genomic scientists and bioinformaticians. Members of this CDWG identify high priority somatic variants in different cancer types that require expert curation and consensus in their clinical interpretation. In order to accurately implement practice guidelines/standards for variant interpretation, the Somatic Cancer CDWG recently established a somatic Variant Curation Expert Panel (VCEP) approval process. Based on their interest and clinical domain expertise, a subset of the CDWG members formed somatic VCEPs to perform authoritative curation on the shortlisted genes-somatic variants within the context of a disease, therapeutic indication or biological pathway. Expert curation within these VCEPs is performed by utilizing guidelines such as those recommended by AMP/ASCO/CAP (Li et al. 2017) and the Somatic Cancer CDWG (Ritter et al. 2016). Wherever necessary, the somatic VCEPs will develop: 1) gene- and disease-specific modifications to address gaps in existing variant assessment guidelines, 2) quantitative approaches for variant interpretation, and 3) implement standardized protocols for annotating somatic variants in genes for a specific disease, drug or biological pathway. Furthermore, ClinGen recently formed the Cancer Variant Interpretation (CVI) committee to provide support, review and feedback on the provisional somatic variant interpretation proposals developed by the VCEPs. The CVI provides somatic VCEPs with a preliminary approval before the final approval by the ClinGen CDWG oversight committee and ultimately ‘expert panel' status in ClinVar, an NCBI-maintained database of clinically relevant gene variants. NTRK fusions in cancer is the first Somatic VCEP going through the ClinGen Somatic Expert Panel approval process. Alterations in the FGFR pathway in GU cancers is the second somatic VCEP under consideration. The Somatic CDWG uses the CIViC (Clinical Interpretation of Variants in Cancer) platform for curation of somatic variants. To date, the CDWG has curated 268 evidence items relating to cancer variants in CIViC, 6 assertions, and 33 evidence source suggestions. The ultimate goal of the Somatic CDWG is to enhance the usability, dissemination and implementation of cancer somatic changes in the ClinGen resource and other cancer variant knowledgebases. Citation Format: Shruti Rao, Deborah Ritter, Arpad Danos, Gordana Raca, Angshumoy Roy, Kilannin Krysiak, Wan-Hsin Lin, Erica Barnell, Matthew McCoy, Beth Pitel, Dmitriy Sonkin, Jue Wang, Seyed Ali Hosseini, Shamini Selvarajah, Ian King, Rashmi Kanagal-Shamana, Xinjie Xu, Jeremy L. Warner, Funda Meric-Bernstam, Jason D. Merker, Marilyn Li, Alex H. Wagner, Malachi Griffith, Obi L. Griffith, Shashikant Kulkarni, Subha Madhavan. ClinGen somatic cancer working group: Disseminating standardized cancer molecular diagnostic data and evidence through global collaboration and expert curation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3215.

Abstract The use of clinical gene sequencing is now commonplace, and genome analysts and molecular pathologists are often tasked with the labor-intensive process of interpreting the clinical significance of large numbers of tumor variants. Numerous independent knowledgebases have been constructed to alleviate this manual burden, however these knowledgebases are non-interoperable. As a result, the analyst is left with a difficult tradeoff: for each knowledgebase used the analyst must understand the nuances particular to that resource and integrate its evidence accordingly when generating the clinical report, but for each knowledgebase omitted there is increased potential for missed findings of clinical significance.The Variant Interpretation for Cancer Consortium (VICC; cancervariants.org) was formed as a driver project of the Global Alliance for Genomics and Health (GA4GH; ga4gh.org) to address this concern. VICC members include representatives from several major somatic interpretation knowledgebases including CIViC, OncoKB, Jax-CKB, the Weill Cornell PMKB, the IRB-Barcelona Cancer Biomarkers Database, and others. Previously, the VICC built and reported on a harmonized meta-knowledgebase of 19,551 biomarker associations of harmonized variants, diseases, drugs, and evidence across the constituent resources.In that study, we analyzed the frequency with which the tumor samples from the AACR Project GENIE cohort would match to harmonized associations. Variant matches increased dramatically from 57% to 86% when broader matching to regions describing categorical variants were allowed. Unlike precise sequence variants with specified alternate alleles, categorical variants describe a collection of potential variants with a common feature, such as “V600” (non-valine alleles at the 600 residue), “Exon 20 mutations” (all non-silent mutations in exon 20), or “Gain-of-function” (hypermorphic alterations that activate or amplify gene activity). However, matching observed sequence variants to categorical variants is challenging, as the latter are typically only described as unstructured text. Here we describe the expressive and computational GA4GH Variation Representation specification (vr-spec.readthedocs.io), which we co-developed as members of the GA4GH Genomic Knowledge Standards work stream. This specification provides a schema for common, precise forms of variation (e.g. SNVs and Indels) and the method for computing identifiers from these objects. We highlight key aspects of the specification and our work to apply it to the characterization of categorical variation, showcasing the variant terminology and classification tools developed by the VICC to support this effort. These standards and tools are free, open-source, and extensible, overcoming barriers to standardized variant knowledge sharing and search. Citation Format: Alex H. Wagner, Reece K. Hart, Larry Babb, Robert R. Freimuth, Adam Coffman, Yonghao Liang, Beth Pitel, Angshumoy Roy, Matthew Brush, Jennifer Lee, Anna Lu, Thomas Coard, Shruti Rao, Deborah Ritter, Brian Walsh, Susan Mockus, Peter Horak, Ian King, Dmitriy Sonkin, Subha Madhavan, Gordana Raca, Debyani Chakravarty, Malachi Griffith, Obi L. Griffith. Harmonization standards from the Variant Interpretation for Cancer Consortium [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1096.