Genetic analysis and identification of new tumor suppressor genes in childhood acute Lymphoblastic leukemia

儿童急性淋巴细胞白血病的遗传分析及新抑癌基因的鉴定

基本信息

批准号：
18591071
负责人：
TAKEUCHI Seisho
金额：
$ 2.43万
依托单位：
Kochi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

1. Long-Term Study of the Clinical Significance of Loss of Heterozygosity in Childhood Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia (ALL) is one of the most common malignancies in childhood, with a widely variable outcome. Differences in the behavior and prognosis of the leukemia suggest that ALL can be divided into several biologic subgroups. We analyzed the loss of heterozygosity (LOH) of 6q, 9p, 11q, and 12p using 31 microsatellite sites to determine their overall frequency and clinical value. We have studied 244 primary ALL samples obtained from the Multicenter Trial ALL-BFM 90 of Childhood ALL group. These patients have now been followed clinically for over 8 years. LOH occured in 169 (69%) individuals in the following frequencies: 6q, 49 patients (20%); 9p, 97 patients (40%); 11q, 29 patients (12%); 12p, 60 patients (25%). Clinical data showed that those with 6q LOH were younger (p=0.01) and had lower WBC counts (P=0.02); patients with 9p LOH more frequently had CNS … More involvement (p=0.01) and T cell phenotype (p=0.0001); individuals with 11q LOH had a good response to induction chemotherapy (p=0.02); those with 12p LOH were younger(1)=0.005), frequently had precursor B ALL (p=0.001), and had a longer event-free survival (p=0.05). Taken together, these data confirm that LOH is a very frequent alteration in childhood ALL.2. Aberrant Methylation in Promoter-associated CpG Islands of Multiple Genes in Acute Lymphoblastic Leukemia Methylation profile was analyzed in ten childhood acute lymphoblastic leukemia (ALL) and nine adult ALL cases. Four genes (p15, p16, RAR〓, FHIT) had methylation in both diseases, four genes (p14, Rb, MLH1, DAPK) showed no methylation in both diseases, and the two genes (APC, RIZ) demonstrated methylation only in adult ALL. Methylation of the RAR〓 was more frequent in adult ALL than childhood ALL (v0.01). The number of patients with methylation of multiple genes was higher in adult ALL than childhood ALL (p=0.006). Moreover, overall frequency of methylation was higher in adult ALL than childhood ALL (p=0.01). Less

1。关于儿童期杂合性丧失的临床意义的长期研究，急性淋巴细胞性白血病急性淋巴细胞白血病（ALL）是儿童期最常见的恶性肿瘤之一，有广泛可变的结果。白血病的行为和预后的差异表明，所有这些都可以分为几个生物学亚组。我们使用31个微卫星位点分析了6q，9p，11q和12p的杂合性（LOH）的损失，以确定其总频率和临床值。我们研究了244个主要样本，这些样本从童年的多中心试验全BFM 90分组中获得。这些患者现已在临床上进行了8年以上。 LOH在以下频率下发生在169名（69％）的人中：6q，49例患者（20％）； 9p，97例患者（40％）； 11q，29例患者（12％）； 12p，60例患者（25％）。临床数据表明，患有6Q LOH的人年轻（p = 0.01），WBC计数较低（p = 0.02）； 9p LOH的患者频繁患有CNS…更多的参与（P = 0.01）和T细胞表型（P = 0.0001）； 11q LOH的个体对诱导化疗有很好的反应（p = 0.02）；那些具有12p LOH的人年轻（1）= 0.005），经常具有前体B全部（P = 0.001），并且无事件生存期较长（P = 0.05）。综上所述，这些数据证实LOH是童年时期经常发生的。2。急性淋巴细胞白血病甲基化甲基化的启动子相关甲基化的异常甲基化在十个儿童期急性淋巴细胞性白血病（全部）和9例成年病例中分析了急性淋巴细胞白血病甲基化甲基化甲基化。四个基因（p15，p16，rar〓，fHIT）在两种疾病中均甲基化，四个基因（p14，rb，mlh1，dapk）在两种疾病中均未显示甲基化，而两种基因（APC，RIZ）仅在成人中仅显示出甲基化。在成年人中，RAR的甲基化比童年时代更频繁（v0.01）。成年人的甲基化患者数量高于童年的所有基因的数量（p = 0.006）。此外，成年人的总体甲基化频率高于所有童年（p = 0.01）。较少的