Aberrant methylation of p16INK4a is an early event in lung cancer and a potential biomarker for early diagnosis
Aberrant methylation of p16INK4a is an early event in lung cancer and a potential biomarker for early diagnosis
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DOI：
10.1073/pnas.95.20.11891
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发表时间：
1998-09-29
影响因子：
11.1
通讯作者：
Herman, JG
中科院分区：
文献类型：
--
作者：
Belinsky, SA;Nikula, KJ;Herman, JG
在许多肿瘤类型中，p16(INK4a) (p16) 肿瘤抑制基因可因启动子区域高甲基化而失活，其中肺癌是美国癌症相关死亡的主要原因。我们已经在肺癌发生的动物模型和人类鳞状细胞癌 (SCC) 中确定了该事件发生的时间，在大鼠中，94% 的腺癌是由烟草特异性致癌物诱发的4-甲基亚硝基氨基-1-(3-吡啶基)-1-丁酮在p16基因启动子处高度甲基化；最重要的是，这种甲基化变化经常在肿瘤的前体病变中检测到：腺瘤和增生性病变。 pld 甲基化的时间在人类 SCC 中得到重现，其中 p16 基因在 75% 与具有这种变化的 SCC 相邻的原位癌病变中协调甲基化。此外，在从基底细胞增生（17%）到鳞状上皮化生（24%）再到原位癌（50%）病变的疾病进展过程中，该事件的频率增加。 p16 的甲基化与肿瘤和前体病变中的表达缺失相关，表明这两个等位基因在功能上均失活。通过检测 7 名癌症患者中的 3 名和 26 名无癌症高风险个体中的 5 名的痰液中的这种变化，验证了使用异常 p16 甲基化检测来识别疾病和/或风险的潜力。这些研究首次表明，表观遗传改变（p16 基因的异常甲基化）可能是肺癌的早期事件，并且可能构成用于早期检测和监测预防试验的新生物标志物。
The p16(INK4a) (p16) tumor suppressor gene can be inactivated by promoter region hypermethylation in many tumor types including lung cancer, the leading cause of cancer-related deaths in the U.S. We have determined the timing of this event in an animal model of lung carcinogenesis and in human squamous cell carcinomas (SCCs), In the rat, 94% of adenocarcinomas induced by the tobacco specific carcinogen 4-methylnitrosamino-1-(3-pyridyl)-1-butanone were hypermethylated at the p16 gene promoter; most important, this methylation change was frequently detected in precursor lesions to the tumors: adenomas, and hyperplastic lesions. The timing for pld methylation was recapitulated in human SCCs where the p16 gene was coordinately methylated in 75% of carcinoma in situ lesions adjacent to SCCs harboring this change. Moreover, the frequency of this event increased during disease progression from basal cell hyperplasia (17%) to squamous metaplasia (24%) to carcinoma in situ (50%) lesions. Methylation of p16 was associated with loss of expression in both tumors and precursor lesions indicating that both alleles were functionally inactivated. The potential of using assays for aberrant p16 methylation to identify disease and/or risk was validated by detection of this change in sputum from three of seven patients with cancer and 5 of 26 cancer-free individuals at high risk. These studies show for the first time that an epigenetic alteration, aberrant methylation of the p16 gene, can be an early event in lung cancer and may constitute a new biomarker for early detection and monitoring of prevention trials.