Genomics of Familial MDS/AML

家族性MDS/AML是一组罕见的与MDS易感性强相关的孟德尔疾病 和/或AML。这些疾病的遗传基础在约50%的这些家庭中被解释为遗传性疾病。 三种基因（RUNX 1、CEBPA或GATA 2）的变体。这些家族中受影响的携带者发生MDS/AML 具有可变的潜伏期和不完全的潜伏期，这表明合作的体细胞突变是 需要转型。我们假设还有其他的高等位率生殖系等位基因， 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，我们将确定新的 与家族性MDS/AML相关的遗传变异。我们聚集了大量的 MDS/AML激酶（>40），其中约一半确定了已知原因。我们将采用创新的 筛查以排除其余家族中的已知原因，然后进行全基因组测序 在所有具有无法解释的家族易感性的病例中鉴定新的变异。我们将识别出 在这些家族中与MDS/AML分离，并在其他家族中检测复制。我们将产生 早发性初治AML病例的扩展家系，确定 MDS/AML和其他癌症，并对这些病例产生的生殖系全基因组序列数据进行挖掘 通过其他GAML项目来确定AML的其他遗传风险等位基因。我们将履行职能 表征新等位基因对造血作用的研究。在具体目标2中，我们将定义 家族性MDS/AML中的体细胞遗传学改变。我们将进行全基因组测序， 来自至少50例家族性MDS/AML的配对肿瘤/正常样本，并比较 这些病例中的体细胞突变转化为新生和治疗相关的MDS/AML。从这件事中获得的知识 项目将告知我们对AML生物学的理解，并导致更好的监测策略， MDS/AML的早期检测和治疗，包括在MDS/AML家族中优化干细胞供体选择， 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.