Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in DICER1 syndrome: a unique variant of the two-hit tumor suppression model.
Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in DICER1 syndrome: a unique variant of the two-hit tumor suppression model.
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DOI：
10.12688/f1000research.6746.1
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发表时间：
2015-01-01
期刊：
影响因子：
--
通讯作者：
Hill, D Ashley
中科院分区：
文献类型：
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作者：
Brenneman, Mark;Field, Amanda;Hill, D Ashley
胸膜肺母细胞瘤（Pleuropulmonary blastoma， PPB）是最常见的儿童肺部肿瘤，通常是多癌易感的第一个指征，dicer1综合征包括一系列其他罕见的儿童和成年早期的良性和恶性肿瘤。dicer1相关肿瘤发生的遗传学是不寻常的，因为肿瘤通常在dicer1的RNase IIIb结构域中的五个特定“热点”密码子中的一个发生新形态错义突变，并在另一个等位基因中发生完全功能丧失（LOF）。我们分析了124名PPB儿童的dicer1突变易感性，并寻找其与临床表型的相关性。超过70%的人遗传或新生生殖系LOF突变，其中大多数截断dicer1开放阅读框。我们发现少数患者没有种系突变，而是嵌合易患dicer1突变。RNase IIIb结构域热点突变的嵌合性定义了一类特殊的dicer1综合征患者，在临床上与种系或嵌合性LOF突变的患者区分开来，因为前者发病更早，并且有许多分散的肿瘤病灶涉及多个综合征器官部位。最后一类患者缺乏易感的种系或花叶突变，疾病仅限于单一的PPB肿瘤，携带肿瘤特异性RNase IIIb和LOF突变。我们认为，在dicer1相关的肿瘤发生中，获得一个新形态的RNase IIIb结构域突变是限速事件，与突变类别相关的不同临床表型反映了在发育过程中获得LOF和RNase IIIb结构域突变的时间顺序。
Pleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition, DICER1syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics of DICER1-associated tumorigenesis are unusual in that tumors typically bear neomorphic missense mutations at one of five specific "hotspot" codons within the RNase IIIb domain of DICER 1, combined with complete loss of function (LOF) in the other allele. We analyzed a cohort of 124 PPB children for predisposing DICER1mutations and sought correlations with clinical phenotypes. Over 70% have inherited or de novogermline LOF mutations, most of which truncate the DICER1open reading frame. We identified a minority of patients who have no germline mutation, but are instead mosaic for predisposing DICER1mutations. Mosaicism for RNase IIIb domain hotspot mutations defines a special category of DICER1syndrome patients, clinically distinguished from those with germline or mosaic LOF mutations by earlier onsets and numerous discrete foci of neoplastic disease involving multiple syndromic organ sites. A final category of patients lack predisposing germline or mosaic mutations and have disease limited to a single PPB tumor bearing tumor-specific RNase IIIb and LOF mutations. We propose that acquisition of a neomorphic RNase IIIb domain mutation is the rate limiting event in DICER1-associated tumorigenesis, and that distinct clinical phenotypes associated with mutational categories reflect the temporal order in which LOF and RNase IIIb domain mutations are acquired during development.