Increased loss of chromosome 9p21 but not p16 inactivation in primary non-small cell lung cancer from smokers.
Increased loss of chromosome 9p21 but not p16 inactivation in primary non-small cell lung cancer from smokers.
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发表时间：
2001-03
期刊：
影响因子：
11.2
通讯作者：
Montserrat Sanchez-Cespedes;P. Decker;K. Doffek;M. Esteller;W. Westra;Enas A. Alawi;James G. Herman-James-G.-Herm
中科院分区：
文献类型：
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作者：
Montserrat Sanchez-Cespedes;P. Decker;K. Doffek;M. Esteller;W. Westra;Enas A. Alawi;James G. Herman-James-G.-Herm
流行病学研究已经证明吸烟与肺癌之间存在因果关系，最近也确定了香烟烟雾中致癌物质的一些遗传靶点。我们进一步研究了吸烟对染色体9p21等位基因缺失频率和p16失活发生率的影响。应用14个微卫星标记对47例非小细胞肺癌患者进行了9p21-24区染色体缺失的检测。此外，通过DNA序列分析、甲基化特异性聚合酶链式反应和免疫组织化学检测p16基因失活。将来自非吸烟者组(n=14)的肿瘤与来自细胞类型、肿瘤分期和性别匹配的吸烟者组(n=33)的肿瘤进行比较。吸烟者(33例吸烟者中有23例，70%)比非吸烟者(14例非吸烟者中有4例，28%)存在明显的p16基因缺失(P=0.01)。吸烟者和不吸烟者之间的p16失活频率没有显著差异(45%比36%)。P16基因纯合性缺失和点突变仅见于吸烟者肿瘤，而非吸烟者肿瘤中p16基因仅通过启动子甲基化失活。因此，p16基因失活在所有非小细胞肺癌中都是常见的事件，但吸烟者和非吸烟者的基因改变机制不同。吸烟和p16基因缺失之间的显著联系确定了吸烟在肺癌发病机制中的其他遗传靶点。
Epidemiological studies have demonstrated a causal association between tobacco use and carcinoma of the lung, and some genetic targets of the carcinogens in cigarette smoke have been defined recently. We further examined the effect of cigarette smoking on the frequency of allelic losses on chromosome 9p21 and the incidence of p16 inactivation. Chromosomal loss at 9p21-24 was determined by microsatellite analysis using 14 markers in 47 patients with non-small cell lung cancer. In addition, p16 gene inactivation was determined by DNA sequence analysis, methylation-specific PCR, and immunohistochemistry. Tumors from a group of nonsmokers (n = 14) were compared with tumors from a group of smokers (n = 33) matched for cell type, tumor stage, and gender. Allelic loss encompassing the p16 locus was present significantly (P = 0.01) more often in smokers (23 of 33 smokers, 70%) than in nonsmokers (4 of 14 nonsmokers, 28%). No significant differences in the frequency of p16 inactivation were observed between smokers and nonsmokers (45% versus 36%). However, homozygous deletion of the p16 gene locus and point mutation of p16 gene were only observed in tumors from smokers, whereas the p16 gene was inactivated in tumors from nonsmokers only through promoter hypermethylation. Thus, inactivation of the p16 gene is a common event in all non-small cell lung cancer, but the mechanism of gene alteration differs between smokers and nonsmokers. The significant link between tobacco and loss of the p16 locus identifies additional genetic targets of smoking in the pathogenesis of lung cancer.