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确认ALK作为大型家族性神经母细胞瘤的易患基因
Identification of ALK as the Major Familial Neuroblastoma Predisposition Gene
Mossë YP, Laudenslager M, Longo L  2009/8/14 20:26:54 
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Nature, 2009,
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Survival rates for the childhood cancer neuroblastoma have not substantively improved despite dramatic escalation in chemotherapy intensity. Like most human cancers, this embryonal malignancy can be inherited, but the genetic etiology of familial and sporadically occurring neuroblastoma was largely unknown. Here we show that germline mutations in the anaplastic lymphoma kinase gene (ALK) explain the majority of hereditary neuroblastomas, and that activating mutations can also be somatically acquired. We first identified a significant linkage signal at the short arm of chromosome 2 (maximum nonparametric LOD=4.23 at rs1344063) using a whole-genome scan in neuroblastoma pedigrees. Resequencing of regional candidate genes identified three separate missense mutations in the tyrosine kinase domain of ALK (G1128A, R1192P and R1275Q) that segregated with the disease in eight separate families. Examination of 491 sporadically occurring human neuroblastoma samples showed that the ALK locus was gained in 22.8%, and highly amplified in an additional 3.3%, and that these aberrations were highly associated with death from disease (P=0.0003). Resequencing of 194 high-risk neuroblastoma samples showed somatically acquired mutations within the tyrosine kinase domain in 12.4%. Nine of the ten mutations map to critical regions of the kinase domain and were predicted to be oncogenic drivers with high probability. Mutations resulted in constitutive phosphorylation consistent with activation, and targeted knockdown of ALK mRNA resulted in profound growth inhibition of 4 of 4 cell lines harboring mutant or amplified ALK, as well as 2 of 6 wild type for ALK. Our results demonstrate that heritable mutations of ALK are the major cause of familial neuroblastoma, and that germline or acquired activation of this cell surface kinase is a tractable therapeutic target for this lethal pediatric malignancy.
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上腹痛20余天——上海中山病例

上海复旦大学附属中山医院消化科  刘黎黎  高虹

 

患者，男性，19岁，因“上腹痛20余天”于2005年12月15日入院。患者22天前开始出现中上腹持续剧烈疼痛，伴大便次数增多，3～4次/天，不成形，黑色，后出现呕吐，呕吐物为黄绿色胆汁样物质，有时低热，诊断性腹穿抽出少量淡血性液体，外院腹部平片示：小肠梗阻。查血见白细胞18.0×109/L，N 88.4%，尿蛋白(＋)，于12天前行剖腹探查术，术中见腹腔内有淡血性液体200 ml，见小肠节段性病变，未见肠坏死及穿孔，行腹腔冲洗引流术，术后予地塞米松、制酸、生长抑素、营养补液、抗感染治疗后，未见好转而转入我院。

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