PDF(Pubmed)
Abstract：
Neurocutaneous melanosis (NCM) is a rare congenital neurocutaneous syndrome characterized by congenital melanocytic nevus of skin and abnormal proliferation of leptomeningeal melanocytes. Early acquisition of post-zygotic somatic mutations has been postulated to underlie the pathogenesis of NCM. The pathogenesis of NCM remains to be fully elucidated, and treatment options have not been established. Here, we report for the first time, multiregional genomic analyses in a 3-year-old autopsied girl with leptomeningeal melanomatosis associated with NCM, in which a ventriculo-peritoneal (VP) shunt was inserted for the treatment of hydrocephalus. The patient expired six months after the onset due to respiratory failure caused by abdominal dissemination via VP shunt. We performed multiregional exome sequencing to identify genomic differences among brain and abdominal tumors, nevus, and normal tissues. A total of 87 somatic mutations were found in 71 genes, with a significantly large number of gene mutations found in the tumor site. The genetic alterations detected in the nevus were only few and not shared with other sites. Three mutations, namely GNAQ R183Q, S1PR3 G89S and NRAS G12V, considered pathogenic, were found, although S1PR3 mutations have not been previously reported in melanocytic tumors. GNAQ and S1PR3 mutations were shared in both tumor and normal sites. Moreover, the mutant allele frequencies of the two mutations were markedly higher in tumor sites than in normal sites, with copy-neutral loss-of-heterozygosity (CN-LOH) occurring in tumor. NRAS mutation was found only in the abdominal tumor and was thought to be responsible for malignant progression in the present case. Multiregional comprehensive genetic analysis may lead to discovering novel driver mutations associated with tumorigenesis and targeted therapy.
摘要：
神经皮肤黑变病（NCM）是一种罕见的先天性神经皮肤综合征，其特征是先天性皮肤黑素细胞痣和软脑膜黑素细胞异常增殖。合子后体细胞突变的早期获得被认为是NCM发病机理的基础。NCM的发病机制有待充分阐明,治疗方案尚未确定。这里,我们第一次报道，一名3岁尸检女孩的多区域基因组分析，患有与NCM相关的软脑膜黑素瘤病，其中插入脑室-腹膜（VP）分流术治疗脑积水。由于通过VP分流引起的腹部播散引起的呼吸衰竭，患者在发病后六个月死亡。我们进行了多区域外显子组测序，以确定大脑和腹部肿瘤之间的基因组差异，痣,和正常组织。在71个基因中共发现87个体细胞突变,在肿瘤部位发现了大量的基因突变。在痣中检测到的遗传改变很少，并且不与其他位点共享。三个突变,即GNAQR183Q，S1PR3G89S和NRASG12V，被认为是致病性的，被发现,尽管S1PR3突变以前在黑素细胞肿瘤中没有报道。GNAQ和S1PR3突变在肿瘤和正常位点共享。此外，两种突变的突变等位基因频率在肿瘤部位明显高于正常部位，在肿瘤中发生拷贝中性杂合性缺失(CN-LOH)。NRAS突变仅在腹部肿瘤中发现，被认为是造成本病例恶性进展的原因。多区域综合遗传分析可能导致发现与肿瘤发生和靶向治疗相关的新型驱动突变。
