The risk of cigarette smoking plays a pivotal role in increasing the incidence rates of lung cancer. This paper sheds new light on modeling the impact of cigarette smoking on lung cancer evolution, especially genetic instability and the number of gene mutations in the genome of stem cells. To handle this issue, we have set up stochastic multi-stage models to fit the data set of the probabilities of current and former smokers from the Nurses' Health Study cohort of females (NHS) and the Health Professionals Follow up Study cohort of men (HPFS). Throughout this paper, we consider both mutation rates and clonal expansion rates as parameters in each compartment. For current and former smokers, three-driver mutations are most likely to take place in the progression of lung cancer under smoking risk. For current smokers, our findings reveal that two to sixteen gene mutations are required to obtain a cancerous cell among men and women in US. Moreover, two to six (eleven) cancer-mutations are available in the pathway to lung cancer among former smokers who have quit smoking for more (less) than ten years for both male and female patients. This highlights that cigarette smoking stimulates the number of driver mutations during lung tumorigenesis in both sexes. It is very crucial to examine the role of cigarette smoking in determining whether genomic instability is an early stage or late stage in the process of lung carcinogenesis.

中文翻译：

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吸烟诱发肺癌的不同机制

吸烟的风险在增加肺癌发病率方面起着举足轻重的作用。本文为模拟吸烟对肺癌进化的影响提供了新的思路，特别是遗传不稳定性和干细胞基因组中基因突变的数量。为了解决这个问题，我们建立了随机多阶段模型，以拟合来自女性护士健康研究队列 (NHS) 和男性健康专业人员跟进研究队列的当前和以前吸烟者的概率数据集（ HPFS）。在整篇论文中，我们将突变率和克隆扩展率都视为每个隔室中的参数。对于现在和以前的吸烟者来说，三驱动突变最有可能发生在吸烟风险下的肺癌进展中。对于现在的吸烟者来说，我们的研究结果表明，美国男性和女性需要 2 到 16 个基因突变才能获得癌细胞。此外，在男性和女性患者戒烟时间超过（少于）十年的前吸烟者中，有两到六（十一）个癌症突变可用于肺癌的途径。这突出表明吸烟会刺激两性肺肿瘤发生过程中驱动突变的数量。检查吸烟在确定基因组不稳定性是肺癌发生过程中的早期阶段还是晚期阶段中的作用非常重要。在男性和女性患者戒烟时间超过（少于）十年的前吸烟者中，有两到六（十一）个癌症突变可用于肺癌的途径。这突出表明吸烟会刺激两性肺肿瘤发生过程中驱动突变的数量。检查吸烟在确定基因组不稳定性是肺癌发生过程中的早期阶段还是晚期阶段中的作用非常重要。在男性和女性患者戒烟时间超过（少于）十年的前吸烟者中，有两到六（十一）个癌症突变可用于肺癌的途径。这突出表明吸烟会刺激两性肺肿瘤发生过程中驱动突变的数量。检查吸烟在确定基因组不稳定性是肺癌发生过程中的早期阶段还是晚期阶段中的作用非常重要。