Genomic Expert Curation Panels for Pediatric Malignancies

项目摘要/摘要 这项提案的目标是发展专家小组，专注于为临床应用挑选证据。 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基因 可能影响其诊断、预后和治疗的个人资料。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列出儿童肿瘤的体细胞变异。新的 需要证据筛选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，我们的应用程序构建在两个突出的 在我们团队的带领下，这一领域的发展。第一，作为Clingen躯体临床领域工作组 (CDWG)我们制定了最小变异水平数据(MVLD)标准，以促进基因的共享和使用 精确肿瘤学中的变种。第二，我们制定了癌症变异的临床解释(CIRITAL) 用于躯体治疗和临床解释的专家众包平台。我们的目标是：(1) 系统地编目常见的、罕见的和新的变异的临床相关性，通过 儿童癌症的基因特异性和基因组规模检测；(2)与Clingen，ClinVar， 制定指导方针的专业组织以及其他相关的全球努力，以翻译和介绍 来自基因组研究人员和临床实验室的知识；以及(3)开发信息学支持 临床可操作性的不同评估、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，我们在过去三年里通过 华盛顿大学、乔治城大学和儿童医院的研究人员之间的克莱根躯体CDWG 洛杉矶医院，包括临床和分子遗传学家，遗传顾问，生物信息学家， 以及基因组数据库专家，以促进基因组数据在儿童癌症中的使用。具体来说，我们将 建立试点不同的治疗专家小组(VCEP)，以评估躯体的临床相关性和可操作性 儿科癌症中的变异。我们最初的重点将是两个疾病领域，具有及时的相关性，儿科 NTRK融合和BCR-ABL1(费城)样B淋巴细胞性白血病(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Strong临床的变体 临床意义、潜在临床意义、未知临床意义及良性或可能良性变异 儿童癌症。我们将调整和加强民间平台，以支持这些专家小组。《公民》 Platform还将以标准格式提供经过整理的证据，以便与ClinVar和 Clingen资源。最后，我们将寻求FDA对开发和管理的证据库的认可 通过这笔赠款。

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.