Familial cancer associated with a polymorphism in ARLTS1
Familial cancer associated with a polymorphism in ARLTS1
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DOI：
10.1056/nejmoa042280
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发表时间：
2005-04-21
影响因子：
158.5
通讯作者：
Croce, CM
中科院分区：
文献类型：
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作者：
Calin, GA;Trapasso, F;Croce, CM
背景：在13号染色体14带的半合子或纯合子缺失的发现在各种肿瘤表明存在一个肿瘤抑制基因位点端粒的RB 1基因。方法：我们研究了216例患者的样本与各种类型的散发性肿瘤或特发性全血细胞减少症，外周血样本109例家族性癌症或多种癌症，和对照组血液样本475健康人或癌症以外的疾病患者。我们进行了功能研究的细胞系缺乏ARLTS 1表达与使用的全长ARLTS 1基因和截断variant.RESULTS：我们发现了一个基因在13 q14，ARLTS 1，ADP-核糖基化因子家族的成员，具有肿瘤抑制基因的属性。我们分析了800份来自散发性或家族性癌症患者和对照组的肿瘤和血细胞的DNA样本，发现无义多态性G446 A的频率与肿瘤和血细胞的DNA样本的频率相关。Trp 149 Stop在对照组和散发性肿瘤患者中相似，但在家族性肿瘤患者中明显高于其他两组（P=0.02;比值比，5.7; 95%置信区间，1.3至24.8）。在我们分析的25%的原发性肿瘤中，ARLTS 1因启动子甲基化而下调。将野生型ARLTS 1转染入A549肺癌细胞抑制了免疫缺陷小鼠的肿瘤形成并诱导了细胞凋亡，而转染截短的ARLTS 1对细胞凋亡和肿瘤抑制的作用有限。微阵列分析显示，野生型和Trp 149 Stop转染克隆有不同的表达profiles.CONCLUSIONS：ARLTS 1的遗传变异使患者易患家族性癌症。
BACKGROUND:The finding of hemizygous or homozygous deletions at band 14 on chromosome 13 in a variety of neoplasms suggests the presence of a tumor-suppressor locus telomeric to the RB1 gene.METHODS:We studied samples from 216 patients with various types of sporadic tumors or idiopathic pancytopenia, peripheral-blood samples from 109 patients with familial cancer or multiple cancers, and control blood samples from 475 healthy people or patients with diseases other than cancer. We performed functional studies of cell lines lacking ARLTS1 expression with the use of both the full-length ARLTS1 gene and a truncated variant.RESULTS:We found a gene at 13q14, ARLTS1, a member of the ADP-ribosylation factor family, with properties of a tumor-suppressor gene. We analyzed 800 DNA samples from tumors and blood cells from patients with sporadic or familial cancer and controls and found that the frequency of a nonsense polymorphism, G446A (Trp149Stop), was similar in controls and patients with sporadic tumors but was significantly more common among patients with familial cancer than among those in the other two groups (P=0.02; odds ratio, 5.7; 95 percent confidence interval, 1.3 to 24.8). ARLTS1 was down-regulated by promoter methylation in 25 percent of the primary tumors we analyzed. Transfection of wild-type ARLTS1 into A549 lung-cancer cells suppressed tumor formation in immunodeficient mice and induced apoptosis, whereas transfection of truncated ARLTS1 had a limited effect on apoptosis and tumor suppression. Microarray analysis revealed that the wild-type and Trp149Stop-transfected clones had different expression profiles.CONCLUSIONS:A genetic variant of ARLTS1 predisposes patients to familial cancer.