A pathogenic mosaic TP53 mutation in two germ layers detected by next generation sequencing.
A pathogenic mosaic TP53 mutation in two germ layers detected by next generation sequencing.
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DOI：
10.1371/journal.pone.0096531
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Anderson J
中科院分区：
文献类型：
--
作者：
Behjati S;Maschietto M;Williams RD;Side L;Hubank M;West R;Pearson K;Sebire N;Tarpey P;Futreal A;Brooks T;Stratton MR;Anderson J
Li-Fraumeni综合征是由生殖系TP 53突变引起的，其临床特征是易患一系列癌症，最常见的是肉瘤、脑肿瘤和白血病。致病性嵌合TP 53突变很少被描述。我们描述了一个2岁的孩子提出了三个独立的癌症超过6个月期间，两个软组织间叶肿瘤和侵略性转移性神经母细胞瘤。由于通过桑格测序对血液DNA进行的TP 53、ALK和SDH突变的常规检测结果为阴性，因此对患者和父母双方的血液DNA进行了全外显子组测序，以更广泛地筛查癌症易感突变。在患者而非父母的DNA中，我们在3-20%的测序读数中发现了c.743 G>A，p.Arg248Gln（CCDS11118.1）TP 53突变，该水平通常不能通过桑格测序检测到。在所有分析的肿瘤样本中检测到该突变的纯合性，并且通过分析该儿童的新生儿血斑DNA证明了种系嵌合体。来自不同胚层的单独肿瘤的发生表明这种从头突变发生在胚胎发生的早期，在原肠胚形成之前。该病例证明了通过下一代深度测序检测到的致病性嵌合体，其出现在胚胎发生的早期阶段。
Li-Fraumeni syndrome is caused by germline TP53 mutations and is clinically characterized by a predisposition to a range of cancers, most commonly sarcoma, brain tumours and leukemia. Pathogenic mosaic TP53 mutations have only rarely been described. We describe a 2 years old child presenting with three separate cancers over a 6 month period; two soft tissue mesenchymal tumors and an aggressive metastatic neuroblastoma. As conventional testing of blood DNA by Sanger sequencing for mutations in TP53, ALK, and SDH was negative, whole exome sequencing of the blood DNA of the patient and both parents was performed to screen more widely for cancer predisposing mutations. In the patient's but not the parents' DNA we found a c.743 G>A, p.Arg248Gln (CCDS11118.1) TP53 mutation in 3–20% of sequencing reads, a level that would not generally be detectable by Sanger sequencing. Homozygosity for this mutation was detected in all tumor samples analyzed, and germline mosaicism was demonstrated by analysis of the child's newborn blood spot DNA. The occurrence of separate tumors derived from different germ layers suggests that this de novo mutation occurred early in embryogenesis, prior to gastrulation. The case demonstrates pathogenic mosaicim, detected by next generation deep sequencing, that arose in the early stages of embryogenesis.
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影响因子：
51.1
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.0802970105
发表时间：
2008-08-12
影响因子：
11.1
作者：
Shlien, Adam;Tabori, Uri;Malkin, David
通讯作者：
Malkin, David