TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke:: Distinct patterns in never, former, and current smokers
TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke:: Distinct patterns in never, former, and current smokers
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DOI：
10.1158/0008-5472.can-05-0551
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发表时间：
2005-06-15
期刊：
影响因子：
11.2
通讯作者：
Hainaut, P
中科院分区：
文献类型：
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作者：
Le Calvez, F;Mukeria, A;Hainaut, P
TP53 突变在吸烟者肺癌中很常见，G:C-to-T:A 颠换的发生率很高，通常被解释为烟草烟雾的诱变指纹。在这项研究中，对从未吸烟者 (n = 40)、以前吸烟者 (n = 27) 和当前吸烟者 (n = 64；主要是重度吸烟者) 的原发性肺肿瘤中的 TP53（外显子 5-9）和 KRAS（密码子 12）进行了分析。通过免疫组织化学分析 p53、环氧合酶-2 (Cox-2) 和硝基酪氨酸 (N-Tyr) 的表达，硝基酪氨酸 (N-Tyr) 是一氧化氮造成的蛋白质损伤的标志物。在 47.5% 从不吸烟者、55.6% 以前吸烟者和 77.4% 目前吸烟者中检测到 TP53 突变。突变的相对风险随着烟草消费的增加而增加（P 线性（趋势）< 0.0001）。 G:C-to-T:A 转换（P = 0.06，当前吸烟者与从不吸烟者）和 A:T-to-G:C 转换（P = 0.03，以前吸烟者与从不吸烟者）始终与吸烟相关。相比之下，G:C 到 A:T 的转变与从不吸烟有关 (P = 0.02)。当前吸烟者中大约一半的突变属于 p53 蛋白的特定结构域，这表明存在共同的结构效应。 KRAS 突变在 131 例病例中的 20 例 (15.3%) 中检测到，与腺癌相比，在鳞状细胞癌中很少见[相对风险 (RR)，0.2； 95% 置信区间 (95% CI), 0.07-1] 并且在前吸烟者中比其他类别更常见。在曾经吸烟者和从不吸烟者之间未发现 Cox-2 表达存在显着差异。然而，高水平的 N-Tyr 在从不吸烟者中比以前更常见（RR，10；95% Cl，1.6-50）。这些结果支持这样的观点：根据吸烟状况，肺部肿瘤发生通过不同的分子机制进行。在从不吸烟的人中，N-Tyr 的积累表明其病因涉及严重炎症。
TP53 mutations are common in lung cancers of smokers, with high prevalence of G:C-to-T:A transversions generally interpreted as mutagen fingerprints of tobacco smoke. In this study, TP53 (exons 5-9) and KRAS (codon 12) were analyzed in primary lung tumors of never (n = 40), former (n = 27), and current smokers (n = 64; mainly heavy smokers). Expression of p53, cyclooxygenase-2 (Cox-2), and nitrotyrosine (N-Tyr), a marker of protein damage by nitric oxide, were analyzed by immunohistochemistry. TP53 mutations were detected in 47.5% never, 55.6% former, and 77.4% current smokers. The relative risk for mutation increased with tobacco consumption (P-linear (trend) < 0.0001). G:C-to-T:A transversions (P = 0.06, current versus never smokers) and A:T-to-G:C transitions (P = 0.03, former versus never smokers) were consistently associated with smoking. In contrast, G:C-to-A:T transitions were associated with never smoking (P = 0.02). About half of mutations in current smokers fell within a particular domain of p53 protein, suggesting a common structural effect. KRAS mutations, detected in 20 of 131 (15.3%) cases, were rare in squamous cell carcinoma compared with adenocarcinoma [relative risk (RR), 0.2; 95% confidence interval (95% CI), 0.07-1] and were more frequent in former smokers than in other categories. No significant differences in Cox-2 expression were found between ever and never smokers. However, high levels of N-Tyr were more common in never than ever smokers (RR, 10; 95% Cl, 1.6-50). These results support the notion that lung tumorigenesis proceeds through different molecular mechanisms according to smoking status. In never smokers, accumulation of N-Tyr suggests an etiology involving severe inflammation.