Genomic Expert Curation Panels for Pediatric Malignancies

项目概要/摘要 该提案的目标是建立专家小组，专注于为临床应用提供证据， 与儿童癌症相关的体细胞突变。儿科人群中的肿瘤具有独特的遗传学特征， 这可能会影响他们的诊断，预后和治疗。目前在代表性方面存在差距 在公共癌症数据库和知识库中发现儿童肿瘤的体细胞变异。新 需要证据管理的方法来确定儿童癌症中的重要突变， 诊断和治疗反应。为了解决这些差距，我们的应用程序建立在两个突出的 在我们团队的带领下，首先，作为ClinGen躯体临床领域工作组， 我们开发了最小变异水平数据（MVLD）标准，以促进基因的共享和使用。 精确肿瘤学的变体。第二，我们开发了癌症变异的临床解释（CIViC） 专家众包平台，用于体细胞治疗和临床解释。我们的目标是：（1） 系统地对通过以下方法确定的常见、罕见和新型变异的临床相关性进行分类： 儿童癌症的基因特异性和基因组规模检测;（2）与ClinGen，ClinVar， 制定准则的专业组织，以及其他相关的全球努力， 来自基因组研究人员和临床实验室的知识;（3）发展信息学支持， 临床可行性的变体评估、信息显示、与相关数据库的接口，以及 传播。为了实现这些目标，我们在过去三年中通过 ClinGen Somatic CDWG在华盛顿大学、乔治敦大学和儿童医院的研究人员中进行了研究。 洛杉矶医院，包括临床和分子遗传学家，遗传咨询师，生物信息学家， 和基因组数据库专家，以促进基因组数据在儿童癌症中的使用。具体来说，我们将 建立试点变异治疗专家小组（VCEP），以评估体细胞癌的临床相关性和可行性 儿科癌症的变异。我们最初的重点将是两个疾病领域，及时相关，儿科 NTRK融合和BCR-ABL 1（费城）样B淋巴母细胞白血病（Ph样B-ALL）的恶性肿瘤。 我们将采用ClinGen现有的VCEP政策和流程来评估强临床 显著性、潜在临床显著性、未知临床显著性和良性或可能的良性变异， 儿童癌症我们将调整和加强CIViC平台，以支持这些专家小组。公民 平台还将以标准格式提供精选证据，以便与ClinVar交换数据， ClinGen资源。最后，我们将寻求FDA对开发和策划的证据库的认可 通过这一赠款。

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.