Myeloid Malignancy Variant Curation Expert Panel

骨髓恶性肿瘤变异管理专家小组

• 批准号: 10173329
• 负责人: LUCY Ann GODLEY
• 金额: $ 30.38万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-20 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10173329
• 关键词: Accounting; Acute Myelocytic Leukemia; Address; Alleles; Allogenic; American Society of Hematology; Biology; Blood Platelets; CEBPA gene; Cancer Detection; Caring; Categories; Childbirth; Classification Scheme; ClinVar; Clinical; Clinical Management; Conflict (Psychology); Consensus; Copy Number Polymorphism; Country; Databases; Defect; Deposition; Development; Diagnostic; Dysmyelopoietic Syndromes; ETV6 gene; Enhancers; Familial Platelet Disorder; Family; Funding; Genes; Germ-Line Mutation; Guidelines; Hematologic Neoplasms; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Immune; Individual; Inherited; Institution; Laboratories; Life; Lymphedema; Mediating; Methods; Monosomy 7; Mutation; Myeloid Leukemia; Myeloproliferative disease; Natural Immunity; Operative Surgical Procedures; Organ; Paper; Pathway interactions; Patient Care; Patients; Phenotype; Population; Predisposition; Process; Prognosis; Publications; Publishing; RNA; RUNX1 gene; Recommendation; Review Literature; Risk; Seeds; Site; Solid Neoplasm; Susceptibility Gene; Syndrome; Teenagers; Testing; Thrombocytopenia; Time; Untranslated RNA; Update; Variant; Work; World Health Organization; base; cancer cell; clinical care; curative treatments; genetic testing; genetic variant; genome resource; innovation; leukemia; member; next generation sequencing; platelet function; precision medicine; transcription factor; working group; young adult

Germline predisposition to hematopoietic malignancies is more common than previously appreciated and is best understood currently for the myeloid malignancies. Variants in genes such as RUNX1, GATA2, ANKRD26, ETV6, CEBPA, and DDX41 are among those commonly identified in patients. Recognizing the emerging importance of germline predisposition to myeloid malignancies, the World Health Organization included this entity as a provisional diagnostic category in its newest leukemia classification scheme. The American Society of Hematology (ASH) and ClinGen partnered in 2017 to pilot a Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) knowing that the consistent functional annotation of gene variants is crucial to clinical management, especially considering that allogeneic hematopoietic stem cell transplantation (HSCT) using related donors is a mainstay of treatment for myeloid leukemias. Drs. Lucy A. Godley and David Wu have co-chaired the MM-VCEP, which first developed RUNX1 variant curation rules, resulting in two publications: one that outlines the rules in detail, and the other that provides a more clinical perspective on how the rules change variant interpretation. The MM-VCEP is now engaged in developing similar rules for GATA2 variants, and to facilitate this process, they are employing the Delphi method to come to consensus on a formal description of GATA2 deficiency syndrome. The MM-VCEP has also been innovative as the first VCEP to develop rules for germline copy number variants and for variants in a non-coding GATA2 enhancer. As a highly motivated and productive group, the MM-VCEP seeks three years of support beyond the ASH funding commitment so that they can continue to curate RUNX1 and GATA2 variants according to our established rules and to develop curation rules for variants in four additional genes that confer risk for myeloid malignancies: (1-2) ANKRD26 and ETV6: Individuals with deleterious variants in ANKRD26 and ETV6 have life-long thrombocytopenia, decreased platelet function, and risk of developing myeloid malignancies, like germline carriers of deleterious RUNX1 mutations, allowing the MM-VCEP to develop these curation rules in one year; (3) CEBPA: Myeloid leukemias with bi-allelic CEBPA mutations have a favorable prognosis, and in about 10% of these cases, one of the CEBPA mutations is a germline mutation, usually the 5’ end mutation. For this reason, germline genetic testing for CEBPA variants is recommended for those whose malignant cells have bi-allelic mutations. (4) DDX41: Germline DDX41 mutations are the most common mutation causing myeloid malignancies, accounting for about 1% of all cases of acute myeloid leukemias. To date, all truncating DDX41 mutations are found as germline alleles, and several alleles are common in particular populations. Thus, the MM-VCEP seeks to continue its important work in providing worldwide standards for consistent variant curation so that patients at risk of developing myeloid malignancies can receive optimal care, especially at the time of consideration of related donors for HSCT; elective surgeries and childbirth for those with platelet defects; as well as appropriate surveillance for cancer detection and organ function.

种系对造血性恶性性的易感性比以前更为普遍，是最好的 了解目前有关骨髓恶mig虫的理解。 Runx1，gata2，ankrd26等基因的变体， ETV6，CEBPA和DDX41在患者中通常鉴定出来。认识新兴 种系对髓样恶性肿瘤的重要性，世界卫生组织包括 实体是其最新白血病分类方案中的临时诊断类别。美国社会 血液学（ASH）和Clingen于2017年合作，试行髓样恶性变种策展专家小组 （MM-VCEP）知道基因变异的一致功能注释对于临床管理至关重要， 特别是考虑到使用相关供体的同种异体造血干细胞移植（HSCT）是 博士。露西·A·戈德利（Lucy A. Godley）和大卫·吴（David Wu）共同主持了MM-VCEP 首先制定了Runx1变体策划规则，导致两个出版物：一个概述了规则 细节，另一个提供了有关规则如何改变变异解释的更临床观点的。 MM-VCEP现在正在制定针对GATA2变体的类似规则，为了促进此过程，它们是 采用Delphi方法对GATA2缺乏综合征的正式描述达成共识。这 MM-VCEP也是创新的，作为制定种系副本编号变体规则的第一个VCEP， 对于非编码GATA2增强子中的变体。作为一个积极进取和富有成效的团队，MM-VCEP寻求 超出灰烬资金承诺以外的三年支持，以便他们可以继续策划Runx1和 GATA2变体根据我们的既定规则，并在另外四个方面制定变体的策划规则 会议风险的髓样恶性肿瘤的基因：（1-2）ANKRD26和ETV6：具有有害变体的个体 在ANKRD26和ETV6中 髓样恶性肿瘤，例如有害Runx1突变的种系载体，允许MM-VCEP发展 这些策划规则在一年内； （3）CEBPA：带有双重性CEBPA突变的髓样白血病具有良好 预后，其中约10％的情况下，CEBPA突变之一是种系突变，通常是5' 最终突变。因此，建议那些CEBPA变体的种系基因测试 恶性细胞具有双期平行性突变。 （4）DDX41：种系DDX41突变是最常见的突变 引起髓样恶质，约占所有急性髓性白血病病例的1％。迄今为止，全部 发现截断的DDX41突变是种系等位基因，并且几个等位基因尤其是常见的 人群。这，MM-VCEP试图继续其重要的工作，以提供全球标准 一致的变体策展，使患有髓样恶性肿瘤风险的患者可以接受最佳护理， 特别是在考虑HSCT相关捐赠者时；为患有的人的选修手术和孩子 血小板缺陷；以及适当的癌症检测和器官功能的监视。