Genomics of Familial MDS/AML

家族性MDS/AML是一组罕见的孟德尔疾病，与MDS的强烈易感性有关 和/或急性髓系白血病。这些疾病的遗传基础在这些家庭中约50%是通过遗传来解释的 三个基因(RUNX1、CEBPA或GATA2)的变异。这些家庭中受影响的携带者会患上MDS/AML 具有可变的潜伏期和不完全的外显，这表明合作的体细胞突变是 转型所必需的。我们假设存在额外的高外显性种系等位基因 解释缺乏已知因果变异的家族性MDS/AML病例。在具体目标1中，我们将确定小说 与家族性MDS/AML相关的遗传变异。我们已经组装了大量的 MDS/AML亲属(&gt；40)，已查明的原因约占一半。我们将使用一种创新的 筛查以排除其余家系中的已知原因，然后进行全基因组测序 在所有有不明原因的家族性倾向的病例中识别新的变异。我们将确定变种， 在这些家系中分离MDS/AML，并在其他家系中检测复制情况。我们将生成 早发性初发AML患者的家系扩大，决定了AML的家族聚集程度 MDS/AML和其他癌症，以及为这些病例生成的种系全基因组序列数据 通过其他GAML项目来确定AML的其他遗传风险等位基因。我们将执行功能 研究新的等位基因对造血的影响。在具体目标2中，我们将定义 家族性MDS/AML的体细胞遗传改变的格局。我们将进行全基因组测序 至少50例家族性MDS/AML患者的肿瘤/正常样本配对，并比较其频谱 这些病例中的体细胞突变导致从头开始和治疗相关的MDS/AML。从这个过程中学到的知识 该项目将使我们了解急性髓细胞白血病的生物学，并导致更好的监测战略， MDS/AML的早期发现和治疗，包括优化的干细胞捐赠者选择 遗传易感性。

Familial MDS/AML is a group of rare Mendelian disorders associated with strong predisposition to MDS and/or AML. The genetic basis of these disorders is explained in ~50% of these families by inherited variants in three genes {RUNX1, CEBPA, or GATA2). Affected carriers in these families develop MDS/AML with variable latency and incomplete penetrance, suggesting that cooperating somatic mutations are required for transformation. We hypothesize that there are additional high penetrance germline alleles that account for familial MDS/AML cases lacking known causal variants. In Specific Aim 1, we will identify novel inherited genetic variants associated with familial MDS/AML. We have assembled a large number of MDS/AML kindreds (>40), with known causes identified in approximately half. We will use an innovative screen to exclude known causes in the remaining families and will then perform whole genome sequencing to identify novel variants in all cases with unexplained familial predisposition. We will identify variants that segregate with MDS/AML in these families and test for replication in other families. We will generate extended pedigrees for early-onset de novo AML cases, determine the extent of familial aggregation of MDS/AML and other cancers, and mine germline whole genome sequence data generated for these cases by other GAML projects to identify additional inherited risk alleles for AML. We will perform functional studies to characterize the effects of novel alleles on hematopoiesis. In Specific Aim 2, we will define the landscape of somatic genetic alterations in familial MDS/AML. We will perform whole genome sequencing of paired tumor/normal samples from at least 50 cases of familial MDS/AML and compare the spectrum of somatic mutations in these cases to de novo and therapy-related MDS/AML. Knowledge gained from this project will inform our understanding ofthe biology of AML, and lead to better strategies for surveillance, early detection, and treatment of MDS/AML, including optimized stem cell donor selection in families with inherited susceptibility.