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首页> 外文期刊>Human Genetics >Detection of low-prevalence somatic TSC2 mutations in sporadic pulmonary lymphangioleiomyomatosis tissues by deep sequencing
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Detection of low-prevalence somatic TSC2 mutations in sporadic pulmonary lymphangioleiomyomatosis tissues by deep sequencing

机译：深度测序检测散发性肺淋巴管平滑肌瘤病组织中低流行性体细胞TSC2突变

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Lymphangioleiomyomatosis (LAM) (MIM #606690) is a rare lung disorder leading to respiratory failure associated with progressive cystic destruction due to the proliferation and infiltration of abnormal smooth muscle-like cells (LAM cells). LAM can occur alone (sporadic LAM, S-LAM) or combined with tuberous sclerosis complex (TSC-LAM). TSC is caused by a germline heterozygous mutation in either TSC1 or TSC2, and TSC-LAM is thought to occur as a result of a somatic mutation (second hit) in addition to a germline mutation in TSC1 or TSC2 (first hit). S-LAM is also thought to occur under the two-hit model involving a somatic mutation and/or loss of heterozygosity in TSC2. To identify TSC1 or TSC2 changes in S-LAM patients, the two genes were analyzed by deep next-generation sequencing (NGS) using genomic DNA from blood leukocytes (n = 9), LAM tissue from lung (n = 7), LAM cultured cells (n = 4), or LAM cell clusters (n = 1). We identified nine somatic mutations in six of nine S-LAM patients (67 %) with mutant allele frequencies of 1.7-46.2 %. Three of these six patients (50 %) showed two different TSC2 mutations with allele frequencies of 1.7-28.7 %. Furthermore, at least five mutations with low prevalence (< 20 % of allele frequency) were confirmed by droplet digital PCR. As LAM tissues are likely to be composed of heterogeneous cell populations, mutant allele frequencies can be low. Our results confirm the consistent finding of TSC2 mutations in LAM samples, and highlight the benefit of laser capture microdissection and in-depth allele analyses for detection, such as NGS.
机译：淋巴管平滑肌肌瘤病（LAM）（MIM＃606690）是一种罕见的肺部疾病，由于异常平滑肌样细胞（LAM细胞）的增殖和浸润而导致与进行性囊性破坏相关的呼吸衰竭。 LAM可以单独发生（散发性LAM，S-LAM），也可以与结节性硬化症复合体（TSC-LAM）合并使用。 TSC是由TSC1或TSC2中的种系杂合突变引起的，除TSC1或TSC2的种系突变（首次命中）外，TSC-LAM被认为是由于体细胞突变（第二次命中）而发生的。 S-LAM也被认为是在涉及TSC2体细胞突变和/或杂合性丧失的两次打击模型下发生的。为了鉴定S-LAM患者的TSC1或TSC2变化，使用来自血液白细胞的基因组DNA（n = 9），来自肺的LAM组织（n = 7），培养的LAM，通过深度下一代测序（NGS）分析了这两个基因单元（n = 4）或LAM单元簇（n = 1）。我们在9名S-LAM患者中有6名（67％）发现了9种体细胞突变，突变等位基因频率为1.7-46.2％。这六位患者中的三位（50％）显示出两个不同的TSC2突变，等位基因频率为1.7-28.7％。此外，通过液滴数字PCR确认了至少五个低流行率的突变（等位基因频率的<20％）。由于LAM组织可能由异质细胞群体组成，因此突变等位基因频率可能很低。我们的结果证实了在LAM样品中TSC2突变的一致发现，并强调了激光捕获显微切割和深入等位基因分析（例如NGS）的优势。

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