Institut Curie, Département de pédiatrie, Paris, France.
Eur J Hum Genet. 2012 Mar;20(3):291-7. doi: 10.1038/ejhg.2011.195. Epub 2011 Nov 9.
Neuroblastic tumours may occur in a predisposition context. Two main genes are involved: PHOX2B, observed in familial cases and frequently associated with other neurocristopathies (Ondine's and Hirschsprung's disease); and ALK, mostly in familial tumours. We have assessed the frequency of mutations of these two genes in patients with a presumable higher risk of predisposition. We sequenced both genes in 26 perinatal cases (prebirth and <1 month of age, among which 10 were multifocal), 16 multifocal postnatal (>1 month) cases, 3 pairs of affected relatives and 8 patients with multiple malignancies. The whole coding sequences of the two genes were analysed in tumour and/or constitutional DNAs. We found three ALK germline mutations, all in a context of multifocal tumours. Two mutations (T1151R and R1192P) were inherited and shared by several unaffected patients, thus illustrating an incomplete penetrance. Younger age at tumour onset did not seem to offer a relevant selection criterion for ALK analyses. Conversely, multifocal tumours might be the most to benefit from the genetic screening. Finally, no PHOX2B germline mutation was found in this series. In conclusion, ALK deleterious mutations are rare events in patients with a high probability of predisposition. Other predisposing genes remain to be discovered.
神经母细胞瘤可能发生在易感性背景下。有两个主要基因参与：PHOX2B，见于家族性病例，常与其他神经嵴病变（翁迪恩氏病和先天性巨结肠）相关；ALK，主要见于家族性肿瘤。我们评估了这些两个基因在假定易感性较高的患者中的突变频率。我们对 26 例围产期病例（产前和<1 个月龄，其中 10 例为多灶性）、16 例多灶性产后（>1 个月）病例、3 对受累亲属和 8 例多发性恶性肿瘤患者的这两个基因进行了测序。对肿瘤和/或正常 DNA 中的两个基因的整个编码序列进行了分析。我们发现了三个 ALK 种系突变，均发生在多灶性肿瘤的背景下。两个突变（T1151R 和 R1192P）是遗传性的，为多个未受影响的患者所共有，因此说明存在不完全外显率。肿瘤发病年龄较轻似乎不是 ALK 分析的相关选择标准。相反，多灶性肿瘤可能最受益于基因筛查。最后，该系列未发现 PHOX2B 种系突变。总之，ALK 有害突变在易感性高的患者中是罕见事件。其他易感基因仍有待发现。
