Newcomb E W, Bayona W, Pisharody S
Department of Pathology, New York University Medical Center, New York 10016, USA.
Mol Carcinog. 1995 Jun;13(2):89-95. doi: 10.1002/mc.2940130205.
N-Methylnitrosourea (NMU)-induced codon 12 Ki-ras mutations were analyzed in premalignant thymic lymphomas from C57BL/6J mice by using a selective polymerase chain reaction amplification strategy. The frequency of codon 12 Ki-ras mutations was 67% (16 of 24) in NMU-treated animals with premalignant stage I disease. Previously, animals with different stages of disease had been analyzed for cytogenetic changes and for mutations in the p53 tumor suppressor gene. The genetic changes observed were early-activating codon 12 G35-->A transition mutations of the Ki-ras gene, followed closely by trisomy 15 and infrequent mutation of the p53 gene late in tumor development. The consistent and early detection of Ki-ras mutations in NMU-treated animals but not in untreated controls suggests that the mutations result from direct carcinogen exposure. Alternate pathways of NMU-induced thymic lymphomagenesis were implicated. One pathway involved putative NMU-induced mutations in other, non-ras oncogenes that cooperate with trisomy 15 to produce similar T-cell tumors. The frequency of p53 gene mutations in human and murine T-cell tumors is similar but low.
采用选择性聚合酶链反应扩增策略，对C57BL/6J小鼠的癌前胸腺淋巴瘤中N-甲基亚硝基脲（NMU）诱导的第12密码子Ki-ras突变进行了分析。在处于癌前I期疾病的NMU处理动物中，第12密码子Ki-ras突变的频率为67%（24例中的16例）。此前，已对处于不同疾病阶段的动物进行了细胞遗传学变化以及p53肿瘤抑制基因突变的分析。观察到的基因变化为Ki-ras基因早期激活的第12密码子G35→A转换突变，紧随其后的是15号染色体三体，以及肿瘤发展后期p53基因的罕见突变。在NMU处理的动物而非未处理的对照中一致且早期检测到Ki-ras突变，这表明这些突变是由直接接触致癌物导致的。这暗示了NMU诱导胸腺淋巴瘤发生的其他途径。一种途径涉及NMU在其他非ras癌基因中诱导的假定突变，这些突变与15号染色体三体协同作用以产生相似的T细胞肿瘤。人类和小鼠T细胞肿瘤中p53基因突变的频率相似但较低。
