Genomic Expert Curation Panels for Pediatric Malignancies

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Project Summary/Abstract The goal of this proposal is to develop expert panels focused on curating evidence for the clinical application of somatic mutations associated with childhood cancers. Tumors in the pediatric population have unique genetic profiles that can affect their diagnosis, prognosis and treatment. There is currently a gap in representation of somatic variants for childhood tumors in public cancer databases and knowledgebases. New approaches for evidence curation are needed to identify important mutations in childhood cancers for both diagnosis and therapy response. To address these gaps, our application builds on two prominent developments in the field led by our team. First, as the ClinGen Somatic Clinical Domain Working Group (CDWG) we developed the Minimal Variant Level Data (MVLD) standard to promote sharing and use of gene variants in precision oncology. Second, we developed the Clinical Interpretation of Variants in Cancer (CIViC) expert crowdsourced platform for somatic curation and clinical interpretation. Our goals are to: (1) systematically catalog the clinical relevance of common, rare, and novel variants identified through gene-specific and genome-scale testing in childhood cancers; (2) partner with ClinGen, ClinVar, guideline-setting professional organizations, and other relevant global efforts to translate and present the knowledge derived from genome researchers and clinical laboratories; and (3) develop informatics support for variant assessment of clinical actionability, information display, interfacing with relevant databases, and dissemination. To accomplish these goals we developed a collaboration over the past three years through the ClinGen Somatic CDWG among researchers at Washington University, Georgetown University, and Children’s Hospital Los Angeles that includes clinical and molecular geneticists, genetic counselors, bioinformaticians, and genomic database experts to advance the use of genomic data in childhood cancers. Specifically, we will establish pilot variant curation expert panels (VCEPs) to assess clinical relevance and actionability of somatic variants in pediatric cancers. Our initial focus will be on two disease areas, with timely relevance, pediatric malignancies with NTRK fusions and BCR-ABL1 (Philadelphia)-like B-lymphoblastic leukemia (Ph-like B-ALL). We will adopt ClinGen’s existing VCEP policies and processes for assessing variants of strong clinical significance, potential clinical significance, unknown clinical significance, and benign or likely benign variants in childhood cancers. We will adapt and enhance the CIViC platform to support these expert panels. The CIViC platform will also provide the curated evidence in standard formats for exchange of data with ClinVar and ClinGen resources. Finally, we will seek FDA recognition for the evidence repository developed and curated through this grant.