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Prevalence and functional consequence of PHOX2B mutations in neuroblastoma

机译：神经母细胞瘤中PHOX2B突变的患病率和功能后果

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PHOX2B is a homeodomain-containing protein that is involved in the development of the peripheral nervous system and is the major disease gene for the rare congenital breathing disorder congenital central hypoventilation syndrome (CCHS). Germline PHOX2B alterations were also recently discovered in neuroblastoma cases with CCHS and/or Hirschsprung disease, but a comprehensive survey for mutational frequency and functional consequence has not been performed. We therefore studied a large panel of hereditary neuroblastomas to understand the frequency and functional effects of PHOX2B mutations. Three of 47 individuals with presumed genetic predisposition to neuroblastoma showed a germline PHOX2B mutation (6.4%). Mutations were also discovered in 2 of 30 human neuroblastoma-derived cell lines, but none of 86 primary tumors from patients with sporadically occurring neuroblastoma. The vast majority of primary tumors showed abundant PHOX2B mRNA expression relative to the remainder of the transcriptome. Consistent with its role as an important neurodevelopmental gene, forced overexpression of wild-type PHOX2B in neuroblastoma cell lines suppressed cell proliferation and synergized with all-trans retinoic acid to promote differentiation. Patient-derived mutant PHOX2B constructs retained the ability to suppress cellular proliferation, but were not able to promote differentiation or activate expression of a known PHOX2B target gene in vitro. These findings show that PHOX2B alterations are a rare cause of hereditary neuroblastoma, but disruption of this neurodevelopmental pathway can interfere with transcription-dependent terminal differentiation. These data also suggest that the genetics of neuroblastoma initiation are complex, and highlight genes involved in normal noradrenergic development as candidate predisposition genes.
机译：PHOX2B是一种含有同源结构域的蛋白质，与周围神经系统的发育有关，是罕见的先天性呼吸障碍先天性中枢通气不足综合征（CCHS）的主要疾病基因。最近在CCHS和/或Hirschsprung病的神经母细胞瘤病例中也发现了生殖细胞PHOX2B的改变，但是尚未对突变频率和功能后果进行全面的调查。因此，我们研究了一大批遗传性神经母细胞瘤，以了解PHOX2B突变的频率和功能影响。在47位具有神经母细胞瘤遗传易感性的个体中，有3位表现出种系PHOX2B突变（6.4％）。在30种人类神经母细胞瘤衍生的细胞系中也发现了2种突变，但在偶发性神经母细胞瘤患者的86种原发性肿瘤中均未发现突变。相对于转录组的其余部分，绝大多数原发性肿瘤表现出丰富的PHOX2B mRNA表达。与它作为重要的神经发育基因的作用一致，在神经母细胞瘤细胞系中强迫野生型PHOX2B的过表达抑制了细胞增殖，并与全反式维甲酸协同促进分化。患者来源的突变体PHOX2B构建体保留了抑制细胞增殖的能力，但在体外无法促进分化或激活已知PHOX2B靶基因的表达。这些发现表明，PHOX2B改变是遗传性神经母细胞瘤的罕见原因，但这种神经发育途径的破坏可能会干扰转录依赖性终末分化。这些数据还表明，神经母细胞瘤起始的遗传学很复杂，并且突出了参与正常去甲肾上腺素能发育的基因作为候选易感基因。

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