Myeloid Malignancy Variant Curation Expert Panel

骨髓恶性肿瘤变异管理专家小组

• 批准号: 10593903
• 负责人: LUCY Ann GODLEY
• 金额: $ 2.33万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593903
• 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; 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; Lymphedema; Mediating; Methods; Monosomy 7; Mutation; Myeloid Leukemia; Myeloproliferative disease; Natural Immunity; Operative Surgical Procedures; Organ; Paper; Pathway interactions; Patient Care; Patients; Persons; Phenotype; Population; Predisposition; Process; Productivity; Prognosis; Publications; Publishing; RNA; RUNX1 gene; Recommendation; Review Literature; Risk; Site; Solid Neoplasm; Susceptibility Gene; Syndrome; Teenagers; Testing; Thrombocytopenia; Time; Untranslated RNA; Update; Variant; Work; World Health Organization; cancer cell; clinical care; curative treatments; forging; 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.

造血系统恶性肿瘤的种系易感性比以前认识的更常见，并且是最好的 目前被理解为骨髓恶性肿瘤。 RUNX1、GATA2、ANKRD26 等基因变异， ETV6、CEBPA 和 DDX41 是患者中常见的基因。认识到新兴的 种系易感性对骨髓恶性肿瘤的重要性，世界卫生组织将其纳入其中 实体作为其最新的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 年合作试点骨髓恶性肿瘤变异治疗专家小组 (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）是一种 粒细胞白血病的主要治疗方法。博士。 Lucy A. Godley 和 David Wu 共同担任 MM-VCEP 主席， 首先开发了 RUNX1 变体管理规则，并产生了两份出版物：一份概述了 RUNX1 变体管理规则 细节，另一个提供了关于规则如何改变变体解释的更临床视角。这 MM-VCEP 现在正在致力于为 GATA2 变体开发类似的规则，为了促进这一过程，他们正在 采用德尔菲法就 GATA2 缺陷综合征的正式描述达成共识。这 MM-VCEP 也具有创新性，是第一个为种系拷贝数变异制定规则的 VCEP 用于非编码 GATA2 增强子中的变体。作为一个积极主动、富有成效的团体，MM-VCEP 致力于 在 ASH 资金承诺之外提供三年的支持，以便他们能够继续策划 RUNX1 和 GATA2变体根据我们既定的规则，并为另外四个变体制定管理规则 导致骨髓恶性肿瘤风险的基因：(1-2) ANKRD26 和 ETV6：具有有害变异的个体 ANKRD26 和 ETV6 中的患者患有终生血小板减少症、血小板功能下降以及发生以下疾病的风险： 骨髓恶性肿瘤，例如有害 RUNX1 突变的种系携带者，使 MM-VCEP 得以发展 这些管理规则在一年内； (3)CEBPA：具有双等位基因CEBPA突变的粒细胞白血病具有有利的 预后，在大约 10% 的病例中，CEBPA 突变之一是种系突变，通常是 5' 末端突变。因此，建议对以下人群进行 CEBPA 变异种系基因检测： 恶性细胞具有双等位基因突变。 (4) DDX41：种系DDX41突变是最常见的突变 引起髓系恶性肿瘤，约占所有急性髓系白血病病例的1%。迄今为止，所有 截短的 DDX41 突变被发现为种系等位基因，并且有几个等位基因特别常见 人口。因此，MM-VCEP 寻求继续其重要工作，为以下领域提供全球标准： 一致的变异治疗，使有罹患骨髓恶性肿瘤风险的患者能够得到最佳护理， 尤其是在考虑相关捐献者进行 HSCT 时；为患有此病的患者进行选择性手术和分娩 血小板缺陷；以及对癌症检测和器官功能的适当监测。