RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML
RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML
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DOI：
10.1182/bloodadvances.2019000901
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发表时间：
2020-03-24
期刊：
影响因子：
7.5
通讯作者：
Scott, Hamish S.
中科院分区：
文献类型：
--
作者：
Brown, Anna L.;Arts, Peer;Scott, Hamish S.
生殖系侏儒相关转录因子1（RUNX 1）突变于1999年首次报道，是家族性血小板疾病伴骨髓恶性肿瘤易感性（FPD-MM）的公认原因。我们提出了在10个新的RUNX 1突变的FPD-MM家族中检测到的临床表型和基因突变。对这些家系的基因组分析检测到2个部分基因缺失、3个新突变和5个复发突变，作为导致FPD-MM的生殖系RUNX 1改变。将本文报道的家系的基因组数据与聚合的已发表数据集相结合，得到130个生殖系RUNX 1家系，这使我们能够研究特定生殖系突变特征是否（类型、位置）可以解释家族性血小板疾病患者和不同HM之间较大的表型异质性。比较可用的家族性（n = 35）和已发表的散发性（n = 137）RUNX 1突变AML患者之间的体细胞突变特征，显示影响第二个RUNX 1等位基因和GATA 2的体细胞突变富集。相反，我们观察到影响NRAS，SRSF 2和DNMT 3A以及与CHIP和表观遗传调控相关的集体基因的体细胞突变数量减少。这是迄今为止对生殖系RUNX 1突变进行的最大规模的聚集和分析，为研究从FPD到MM的表型差异和疾病进展的潜在因素提供了独特的机会。
First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1 -mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.