Westra W H, Slebos R J, Offerhaus G J, Goodman S N, Evers S G, Kensler T W, Askin F B, Rodenhuis S, Hruban R H
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
Cancer. 1993 Jul 15;72(2):432-8. doi: 10.1002/1097-0142(19930715)72:2<432::aid-cncr2820720219>3.0.co;2-#.
Point mutations in codon 12 of the K-ras protooncogene occur more frequently in lung adenocarcinomas from smokers (30%) than they do in lung adenocarcinomas from nonsmokers (7%), suggesting that smoking is an important factor in the induction of these mutations. The lack of well defined "early" premalignant or in situ glandular neoplasms of the lung, however, has not permitted direct evaluation of the chronology of ras activation in the development of lung adenocarcinomas. To circumvent the need to evaluate precursor lesions, we examined lung adenocarcinomas from former smokers for point mutations in K-ras.
Mutations in codon 12 of K-ras were detected using polymerase chain reaction amplification and mutation-specific oligonucleotide probes. The types and frequencies of mutations found in adenocarcinomas obtained from 57 former smokers were compared to those found in 27 adenocarcinomas from patients who never smoked and to those found in 27 adenocarcinomas from patients who were current smokers.
The overall prevalence of K-ras point mutations in lung adenocarcinomas obtained from former smokers (32%) was not different from that seen in adenocarcinomas from patients who were current smokers (30%, P = 0.83), and was greater than that seen in adenocarcinomas from patients who never smoked (7%, P = 0.015). This pattern was independent of the duration of abstinence from smoking. Furthermore, the predominant type of mutation found in tumors from former smokers was a guanine-to-thymine transversion, the specific type of mutation induced by benzo(a)pyrene, one of the chemical carcinogens found in tobacco smoke.
These findings support previous findings that suggest that codon 12 of the K-ras oncogene may be a specific target of the mutagenic activity of tobacco smoke, and suggest that DNA alterations at this site can occur early and irreversibly during the development of adenocarcinomas of the lung.
K-ras原癌基因第12密码子的点突变在吸烟者的肺腺癌中出现的频率（30%）高于非吸烟者的肺腺癌（7%），这表明吸烟是诱导这些突变的一个重要因素。然而，由于缺乏明确界定的肺部“早期”癌前或原位腺性肿瘤，无法直接评估ras激活在肺腺癌发生过程中的时间顺序。为了避免评估前体病变的必要性，我们检测了曾吸烟者肺腺癌中的K-ras点突变。
使用聚合酶链反应扩增和突变特异性寡核苷酸探针检测K-ras第12密码子的突变。将57例曾吸烟者的腺癌中发现的突变类型和频率与27例从不吸烟者的腺癌以及27例现吸烟者的腺癌中发现的进行比较。
曾吸烟者肺腺癌中K-ras点突变的总体发生率（32%）与现吸烟者腺癌中的发生率（30%，P = 0.83）无差异，且高于从不吸烟者腺癌中的发生率（7%，P = 0.015）。这种模式与戒烟时间无关。此外，曾吸烟者肿瘤中发现的主要突变类型是鸟嘌呤到胸腺嘧啶的颠换，这是烟草烟雾中发现的化学致癌物苯并(a)芘诱导的特定突变类型。
这些发现支持了先前的研究结果，即K-ras癌基因第12密码子可能是烟草烟雾诱变活性的特定靶点，并表明该位点的DNA改变可能在肺腺癌发生过程中早期且不可逆地发生。
