ENVIRONMENTAL EXPOSURES AND RAS MUTATIONS IN LEUKEMIA

环境暴露和 RAS 突变导致白血病

• 批准号: 2377915
• 负责人: LESLIE L ROBISON
• 金额: $ 38.91万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-03-01 至 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2377915
• 关键词: X ray; acute lymphocytic leukemia; acute myelogenous leukemia; alcohols; carcinogenesis; clinical research; drug /agent; electromagnetic radiation; environment related neoplasm /cancer; gel electrophoresis; gene environment interaction; gene mutation; human data; interview; molecular oncology; nucleic acid hybridization; oligonucleotides; pediatric neoplasm /cancer; pesticides; polymerase chain reaction; protooncogene; radionuclides; radon; solvents; statistics /biometry; tobacco

A variety of physical and chemical carcinogens have been demonstrated to induce ras gene mutations in both human and animal tumor models. It has recently been reported that ras mutation-positive adult acute myeloid leukemia (AML) is strongly associated with specific occupational exposures. The overall objective of this Childrens Cancer Group (CCG) project is to define the relationship between reported and measured environmental exposures and the presence or absence of ras gene mutations in leukemic blasts from a large population of children (n=244O) diagnosed with acute lymphoblastic leukemia (ALL) and AML. Utilizing the extensive exposure data collected through two CCG case-control epidemiologic investigations and by conducting molecular studies of proto-oncogenes K- ras and N-ras in malignant blast cells from diagnostic bone marrow specimens, it will be possible to test the following hypotheses: (1) In utero and/or post-natal exposure to specific environmental agents are associated with an increased risk of ras p21 mutation in childhood ALL and AML. Environmental agents to be tested include: solvents, petroleum products, pesticides, medications, alcohol, tobacco products, x-rays, low frequency electromagnetic field radiation and radon; (2) Associations identified differ according to the morphologic/biologic features of the leukemia; (3) The mutational spectra of ras mutations is specific for individual environmental exposures; and (4) Cases positive for ras gene mutation have a poorer event free-survival than cases negative for ras gene mutation, independent of other known prognostic factors. K-ras and N-ras gene mutations in codons 12, 13, and 61 from bone marrow cells will be measured using material available from the CCG Biopathology Center, Leukemia Reference Laboratories and primary treatment institutions. Statistical analyses will be performed to compare the environmental exposures of cases with ras mutation to those cases without ras mutation (case-case comparison) and to compare both case groups to their initially matched normal controls (case-matched control comparison) as well as to the control group as whole (case-pooled control comparison). The proposed investigation of ras gene mutations in childhood leukemia, utilizing the unique resources available through the CCG, will provide important data regarding ras p21 mutations as a potential biologic indicator of exposure to specific environmental agents in childhood acute leukemia cases. Analysis of the mutational spectra of ras proto-oncogenes, in conjunction with the environmental exposure data, may provide new insights into the molecular etiology of childhood acute leukemias.

已经证明了多种物理和化学致癌物 在人类和动物肿瘤模型中诱导RAS基因突变。它有 最近有报道称RAS突变阳性成人急性髓样 白血病（AML）与特定职业密切相关 暴露。该儿童癌组（CCG）的总体目标 项目是为了定义报告与测量之间的关系 环境暴露以及RAS基因突变的存在或不存在 在大量儿童（n = 244o）的白血病中 伴有急性淋巴细胞白血病（ALL）和AML。 利用大量 通过两个CCG病例对照流行病学收集的暴露数据 研究并通过进行原始基因的分子研究K- 来自诊断骨髓的恶性爆炸细胞中的RAS和N-RAS 标本，可以测试以下假设：（1） 子宫和/或产后暴露于特定的环境药物是 与童年时期RAS P21突变的风险增加有关 和AML。 要测试的环境代理包括：溶剂，石油 产品，农药，药物，酒精，烟草产品，X射线，低 频率电磁场辐射和ra； （2）协会 根据 白血病; （3）RAS突变的突变光谱是特异性的 个人环境暴露； （4）RAS基因阳性的病例 突变的事件自由生存较差，而RAS的阴性为阴性 基因突变，与其他已知的预后因素无关。 k-ras和 来自骨髓细胞的密码子12、13和61中的N-RAS基因突变将会 使用CCG生物病理学中心可用的材料测量， 白血病参考实验室和初级治疗机构。 将进行统计分析以比较环境 暴露于RAS突变的病例暴露于没有RAS突变的情况下 （病例比较），并将两个情况组与最初进行比较 匹配的正常对照（案例匹配的对照比较）以及 对照组作为整体（病例控制对照比较）。提议 利用儿童白血病中RAS基因突变的研究 CCG可用的独特资源将提供重要的数据 关于RAS P21突变作为暴露的潜在生物学指标 在儿童急性白血病病例中特定的环境药物。 分析Ras原始基因的突变光谱，结合 有了环境暴露数据，可以为您提供新的见解 儿童急性白血病的分子病因。