Kim Duk-Hwan, Kim Jin Seuk, Ji Yong-Ick, Shim Young Mog, Kim Hojoong, Han Joungho, Park Joobae
Center for Genome Research, Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea 135-710.
Cancer Res. 2003 Jul 1;63(13):3743-6.
Cigarette smoking is the most common cause of lung cancer. The greatest risk of lung cancer is among those who started smoking early in life and continued throughout their lives. However, the molecular mechanisms responsible for the susceptibility to lung cancer in the young smoker are not clear. Recently, several groups have reported that the hypermethylation of CpG islands is associated with exposure to tobacco smoke. We studied the association between the age at starting smoking and hypermethylation of p14, p16, and RASSF1A promoters in 204 primary non-small cell lung cancer patients. We also examined whether hypermethylation of the RASSF1A promoter is an independent prognostic factor. Methylation rates in the 204 samples were detected in 9% for p14, 27% for p16, and 32% for RASSF1A. There was no relationship between the hypermethylation of p14 and p16 and the age at starting smoking. However, hypermethylation of the RASSF1A promoter was found to be significantly associated with the age at starting smoking (P = 0.001). No relationship was found between the methylation status of the RASSF1A promoter and other smoking variables, such as pack-years, smoking status, and the duration of smoking. The age at starting smoking in patients with hypermethylation of RASSF1A was earlier than that of patients without hypermethylation of the RASSF1A promoter (19 +/- 8 versus 25 +/- 7; P = 0.001). Young smokers who started smoking before age 19 were 4.23 times [95% confidence interval (CI) = 1.03-9.67; P = 0.001] more likely to have hypermethylation of the RASSF1A promoter than smokers who started smoking after the age of 19. Furthermore, hypermethylation of the RASSF1A promoter was found to be associated with a poor prognosis in non-small cell lung cancer patients at stages 1 and 2 (P = 0.02 and 0.01, respectively; Log-rank test). The hazard of failure was approximately 3.27 times higher for patients with hypermethylation of the RASSF1A promoter than for those without hypermethylation of the RASSF1A promoter (95% CI = 1.42-8.71; P = 0.01). Young smokers who started the habit before the age of 19 also had a poorer prognosis than those who started after the age of 19 (hazard ratio = 2.14, 95% CI = 1.22-9.11; P = 0.02). Our results suggest that starting cigarette smoking at an early age is associated with hypermethylation of the RASSF1A promoter and that hypermethylation of the RASSF1A promoter may be an independent prognostic factor in primary non-small cell lung cancer.
吸烟是肺癌最常见的病因。肺癌风险最高的人群是那些早年开始吸烟且终生持续吸烟的人。然而，年轻吸烟者易患肺癌的分子机制尚不清楚。最近，有几个研究小组报告称，CpG岛的高甲基化与接触烟草烟雾有关。我们研究了204例原发性非小细胞肺癌患者开始吸烟的年龄与p14、p16和RASSF1A启动子高甲基化之间的关联。我们还检查了RASSF1A启动子的高甲基化是否为独立的预后因素。在204个样本中，p14的甲基化率为9%，p16为27%，RASSF1A为32%。p14和p16的高甲基化与开始吸烟的年龄之间没有关系。然而，发现RASSF1A启动子的高甲基化与开始吸烟的年龄显著相关（P = 0.001）。未发现RASSF1A启动子的甲基化状态与其他吸烟变量之间存在关系，如吸烟包年数、吸烟状态和吸烟持续时间。RASSF1A高甲基化患者开始吸烟的年龄早于RASSF1A启动子未发生高甲基化的患者（19±8岁对25±7岁；P = 0.001）。19岁之前开始吸烟的年轻吸烟者发生RASSF1A启动子高甲基化的可能性是19岁之后开始吸烟的吸烟者的4.23倍[95%置信区间（CI）= 1.03 - 9.67；P = 0.001]。此外，发现RASSF1A启动子的高甲基化与Ⅰ期和Ⅱ期非小细胞肺癌患者的预后不良有关（分别为P = 0.02和0.01；对数秩检验）。RASSF1A启动子高甲基化的患者失败风险比未发生RASSF1A启动子高甲基化的患者高约3.27倍（95% CI = 1.42 - 8.71；P = 0.01）。19岁之前开始吸烟的年轻吸烟者的预后也比19岁之后开始吸烟的吸烟者差（风险比 = 2.14，95% CI = 1.22 - 9.11；P = 0.02）。我们的结果表明，早年开始吸烟与RASSF1A启动子的高甲基化有关，且RASSF1A启动子的高甲基化可能是原发性非小细胞肺癌的一个独立预后因素。
