Myeloid Malignancy Variant Curation

骨髓恶性肿瘤变异治疗

• 批准号: 10907993
• 负责人: LUCY Ann GODLEY
• 金额: $ 26.63万
• 依托单位: NORTHWESTERN UNIVERSITY AT 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10907993
• 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生殖系易感性比以前认识到的更常见， 目前被认为是髓系恶性肿瘤。基因如RUNX 1、GATA 2、ANKRD 26、 ETV 6、CEBPA和DDX 41是患者中常见的病毒。认识到正在出现的 生殖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 实体作为其最新白血病分类方案中的临时诊断类别。美国社会 2017年，血液学研究所（ASH）和ClinGen合作，试点骨髓增生异常病毒治疗专家小组 （MM-VCEP）知道基因变异的一致功能注释对临床管理至关重要， 特别是考虑到使用相关供体的异基因造血干细胞移植（HSCT）是一种治疗造血干细胞移植的方法。 是治疗骨髓性白血病的支柱。Lucy A.博士戈德利和大卫吴共同主持了MM-VCEP， 它首先制定了RUNX 1变体策展规则，并出版了两份出版物：一份概述了 另一个提供了关于规则如何改变变体解释的更临床的观点。的 MM-VCEP目前正在为GATA 2变体制定类似的规则，为了促进这一进程， 采用德尔菲法对GATA 2缺乏综合征的正式描述达成共识。的 MM-VCEP作为第一个为种系拷贝数变异制定规则的VCEP也具有创新性， 对于非编码GATA 2增强子中的变体。作为一个积极性和生产力很高的团体，MM-VCEP寻求 在ASH资助承诺之外提供三年的支持，以便他们能够继续策划RUNX 1， GATA 2变体根据我们建立的规则，并制定了四个额外的变体策展规则 赋予骨髓恶性肿瘤风险的基因：（1-2）ANKRD 26和ETV 6：具有有害变体的个体 在ANKRD 26和ETV 6中，具有终身血小板减少症、血小板功能降低和发展成 骨髓恶性肿瘤，如有害RUNX 1突变的生殖系携带者，允许MM-VCEP发展 （3）CEBPA：具有双等位基因CEBPA突变的髓系白血病具有有利的 在这些病例中，约10%的CEBPA突变是种系突变，通常是5'端突变。 终止突变出于这个原因，CEBPA变体的种系基因检测建议用于那些 恶性细胞具有双等位基因突变。(4)DDX 41：生殖系DDX 41突变是最常见的突变 引起骨髓恶性肿瘤，约占所有急性骨髓性白血病病例的1%。迄今为止，所有 截断DDX 41突变被发现作为生殖系等位基因，并且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，为以下方面提供全球标准： 一致的变异治疗，以便有发生骨髓恶性肿瘤风险的患者可以接受最佳护理， 特别是在考虑HSCT的相关供体时;对于那些患有HSCT的患者， 血小板缺陷;以及对癌症检测和器官功能的适当监测。

项目成果

Revision of RUNX1 variant curation rules.

• DOI: 10.1182/bloodadvances.2022008017
• 发表时间: 2022-08-23
• 期刊: BLOOD ADVANCES
• 影响因子: 7.5
• 作者: Feurstein, Simone;Luo, Xi;Shah, Mancy;Walker, Taylor;Mehta, Nikita;Wu, David;Godley, Lucy A.
• 通讯作者: Godley, Lucy A.