Taylor J A, Sandler D P, Bloomfield C D, Shore D L, Ball E D, Neubauer A, McIntyre O R, Liu E
Environmental and Molecular Epidemiology Section, National Institute of Environmental Health Sciences, Research Triangle Park, N.C. 27709.
J Natl Cancer Inst. 1992 Nov 4;84(21):1626-32. doi: 10.1093/jnci/84.21.1626.
Epidemiologic studies of acute myeloid leukemias (AMLs) show small increases in risk of disease associated with certain occupations and chemical exposures.
This study was designed to determine whether the presence of mutationally activated ras oncogenes in AML are associated with occupational and chemical exposures.
We interviewed 62 patients with newly diagnosed AML (or their next-of-kin), all of whom were enrolled in a national multicenter clinical trial, and 630 healthy control subjects. DNA extracted from patients' pretreatment bone marrow samples was amplified by using the polymerase chain reaction and probed with allele-specific oligonucleotides for activating point mutations at the 12th, 13th, and 61st codons of three protooncogenes: H-ras (also known as HRAS), K-ras (also known as KRAS2), and N-ras (also known as NRAS).
Patients with ras mutation-positive AML had a higher frequency (six of 10 patients) of working 5 or more years in an a priori high-risk occupation than did patients with ras mutation-negative AML (eight of 52; odds ratio [OR] = 6.8; 95% confidence interval [CI] = 1.3-36). Patients with ras mutation-positive AML were more likely than patients with ras mutation-negative AML to have breathed chemical vapor on the job (OR = 9.1; 95% CI = 1.3-64) or to have had skin contact with chemicals (OR = 6.9; 95% CI = 1.3-37). When ras-positive patients were compared with healthy control subjects, the ORs for occupation and occupational exposures remained elevated, while patients with ras mutation-negative AML showed no increased risk when compared with control subjects.
Activation of ras proto-oncogenes may identify an etiologic subgroup of AML caused by occupation and chemical exposure.
Disease etiology may be better understood if epidemiologic measures of exposure are integrated with molecular assays of the genetic defects responsible for cancer initiation and promotion.
急性髓系白血病（AML）的流行病学研究表明，某些职业和化学暴露与疾病风险的小幅增加有关。
本研究旨在确定AML中突变激活的ras癌基因的存在是否与职业和化学暴露有关。
我们采访了6名新诊断为AML的患者（或其近亲），他们均参加了一项全国多中心临床试验，以及630名健康对照者。从患者预处理的骨髓样本中提取的DNA通过聚合酶链反应进行扩增，并用等位基因特异性寡核苷酸探测三个原癌基因（H-ras，也称为HRAS；K-ras，也称为KRAS2；N-ras，也称为NRAS）第12、13和61密码子处的激活点突变。
与ras突变阴性的AML患者（52例中的8例）相比，ras突变阳性的AML患者在先验高危职业中工作5年或更长时间的频率更高（10例患者中的6例）；优势比（OR）=6.8；95%置信区间（CI）=1.3-36。与ras突变阴性的AML患者相比，ras突变阳性的AML患者在工作中接触化学蒸气的可能性更大（OR=9.1；95%CI=1.3-64）或皮肤接触化学物质的可能性更大（OR=6.9；95%CI=1.3-37）。当将ras阳性患者与健康对照者进行比较时，职业和职业暴露的OR值仍然升高，而与对照者相比，ras突变阴性的AML患者未显示出风险增加。
ras原癌基因的激活可能确定了由职业和化学暴露引起的AML的一个病因亚组。
如果将暴露的流行病学测量与负责癌症发生和发展的遗传缺陷的分子检测相结合，可能会更好地理解疾病病因。
