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. 儿童急性淋巴细胞白血病杂合性缺失的临床意义的长期研究急性淋巴细胞白血病（ALL）是儿童期最常见的恶性肿瘤之一，其白血病的行为和预后差异很大。表明 ALL 可分为几个生物学亚组，我们分析了 6q 的杂合性丢失 (LOH)，我们使用 31 个微卫星位点研究了 9p、11q 和 12p 的总体频率和临床价值，研究了从儿童 ALL 组的多中心试验 ALL-BFM 90 中获得的 244 个主要 ALL 样本，这些患者现已进行超过 8 次临床随访。 169 名患者 (69%) 中出现 LOH，频率如下：6q，49 名患者 (20%)；9p，97 名患者。 (40%)；11q，29 名患者 (12%)；12p，60 名患者 (25%) 临床数据显示，患有 6q LOH 的患者年龄较小 (p=0.01)，且 WBC 计数较低 (P=0.02)。具有 9p LOH 的个体更常有 CNS 受累 (p=0.01) 和 T 细胞表型 (p=0.0001)；具有 11q LOH 的个体对诱导化疗有良好的反应（p=0.02）；患有 12p LOH 的患者更年轻（1）=0.005），经常患有前体 B ALL（p=0.001），并且无事件生存期较长（p=0.05）总而言之，这些数据证实 LOH 是急性儿童 ALL.2 启动子相关的多基因 CpG 岛的异常甲基化中非常常见的改变。对 10 例儿童急性淋巴细胞白血病 (ALL) 和 9 例成人 ALL 病例中的淋巴细胞白血病甲基化谱进行了分析。四种基因（p15、p16、RAR〓、FHIT）在两种疾病中均具有甲基化，四种基因（p14、Rb、MLH1、DAPK）。在两种疾病中均未表现出甲基化，并且这两个基因（APC、RIZ）仅在成人 ALL 中表现出甲基化。 RAR〓在成人 ALL 中比儿童 ALL 中更常见 (v0.01) 成人 ALL 中多基因甲基化的患者数量比儿童 ALL 中更高 (p=0.006) 此外，成人中甲基化的总体频率更高。 ALL 比儿童期 ALL 少 (p=0.01)。