Identification of USP9X as a leukemia susceptibility gene.
Identification of USP9X as a leukemia susceptibility gene.
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DOI：
10.1182/bloodadvances.2023009814
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发表时间：
2023-08-22
期刊：
影响因子：
7.5
通讯作者：
中科院分区：
文献类型：
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作者：
我们确定USP9X是一种女性特有的B细胞ALL易感基因，与多种先天性畸形相关。在散发性的儿童B细胞ALL中，USP9X在男性和女性中都起到了肿瘤抑制基因的作用。我们最近报道，患有多发性出生缺陷的儿童患儿童期癌症的风险明显更高。我们对这项研究中患有出生缺陷和癌症的先证者及其父母进行了全基因组测序。结构变异分析发现，在一名患有多发性出生缺陷、发育迟缓和B细胞急性淋巴细胞白血病(B-ALL)的女性先证者中，存在一种新的5kb从头杂合性基础酶缺失，重叠于USP9X的催化结构域。她的表型与女性限制性X连锁综合征智力发育障碍-99(MRXS99F)一致。包括以前报道的女性先证者(n=42)的基因-表型分析表明，患有B-ALL的MRXS99F先证者(n=3)与功能丧失(LoF)USP9X变异和多个异常的受试者聚集在一起。这些女性先证者中B-ALL的累积发病率(7.1%)显著高于监测、流行病学和最终结果数据库中年龄和性别匹配的队列(0.003%)(P<0.05)。目前还没有在男性中发现LOF变异的报道。带有亚形错义变异的男性有神经发育障碍，没有出生缺陷或白血病风险。相比之下，在散发性B-ALL中，男性和女性都会发生体细胞LoF USP9X突变，并且在两性白血病样本中的表达水平相似(P=0.54)，其中表达最高的是具有额外X染色体拷贝的女性患者。总体而言，我们将USP9X描述为一种新的女性特异性白血病易感基因，与多种先天性、神经发育异常和B-ALL风险相关。相反，USP9X在散发性的儿童B-ALL中是一种肿瘤抑制基因，在高危B-ALL患者中低表达与较差的存活率相关。
We identify USP9X as a female-specific B-cell ALL susceptibility gene associated with multiple congenital anomalies. In sporadic pediatric B-cell ALL, USP9X acts a tumor suppressor gene in both males and females. We recently reported that children with multiple birth defects have a significantly higher risk of childhood cancer. We performed whole-genome sequencing on a cohort of probands from this study with birth defects and cancer and their parents. Structural variant analysis identified a novel 5 kb de novo heterozygous inframe deletion overlapping the catalytic domain of USP9X in a female proband with multiple birth defects, developmental delay, and B-cell acute lymphoblastic leukemia (B-ALL). Her phenotype was consistent with female-restricted X-linked syndromic intellectual developmental disorder-99 (MRXS99F). Genotype-phenotype analysis including previously reported female probands (n = 42) demonstrated that MRXS99F probands with B-ALL (n = 3) clustered with subjects with loss-of-function (LoF) USP9X variants and multiple anomalies. The cumulative incidence of B-ALL among these female probands (7.1%) was significantly higher than an age- and sex-matched cohort (0.003%) from the Surveillance, Epidemiology, and End Results database (P < .0001, log-rank test). There are no reports of LoF variants in males. Males with hypomorphic missense variants have neurodevelopmental disorders without birth defects or leukemia risk. In contrast, in sporadic B-ALL, somatic LoF USP9X mutations occur in both males and females, and expression levels are comparable in leukemia samples from both sexes (P = .54), with the highest expressors being female patients with extra copies of the X-chromosome. Overall, we describe USP9X as a novel female-specific leukemia predisposition gene associated with multiple congenital, neurodevelopmental anomalies, and B-ALL risk. In contrast, USP9X serves as a tumor suppressor in sporadic pediatric B-ALL in both sexes, with low expression associated with poorer survival in patients with high-risk B-ALL.
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影响因子：
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作者：
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