br ACCEPTED MANUSCRIPT br Discussion
In this study, we found that patients with lung cancer in the failure to quit smoking group had a significantly higher smoking duration and younger initial smoking age than those in the successful smoking cessation group. Moreover, we first reported that patients with the GG genotype in CHRNA3 (rs578776), the AA genotype in CHRNA4 (rs1044396) and the CC genotype in CHRNA4 (rs2229959) were more likely to quit smoking successfully.
The CARDIA longitudinal study from 1985 to 2011 reported that age at baseline was associated with the failure to quit smoking by the end of the study, and more relapse was observed among those who gave up smoking16; 18-24 years old vs 25-30 years old, always smoked 30.1% vs 23.1% and unsuccessful quitter 15.0% vs 10.4%. In the current study, the age smoking initiation in the failure to quit smoking group was 18 years old, which was significantly younger than that in the successful smoking cessation group (21 years old). This result was consistent with the findings of the CARDIA study. Smoking onset may be genetically determined. Ling et al. reported that a polymorphism of the dopamine transporter gene (SLC6A3) may play important roles in smoking onset, and there may be an interactive effect between SLC6A3 and early smoking onset17.
Nicotine could increase the risk of cancer by promoting the growth and survival of malignant cells and protect them from chemotherapy or radiotherapy-induced apoptosis. The nicotinic 3X FLAG Peptide (ACh) receptors (nAChRs) could also upregulate the proliferative and survival genes on the cell membrane of lung cancer 18. Several studies have identified the CHRNA5–CHRNA3 –CHRNB4 gene cluster not only with the severity of smoking but also with nicotine dependence 19, 20. CHRNA5 also contributes to nicotine-induced tumour cell proliferation21. Schwartz et al. reported that SNPs in the CHRNA3 and CHRNA5 regions contributed to lung cancer risk and had racial differences in Americans22. CHRNA5 (rs16969968) and CHRNA3 (rs578776) had a strong association with nicotine dependence in the normal population23. Tomaz et al. 24 found that females with GA and AA genotypes of CHRNA5 (rs16969968) polymorphisms had higher success rates in smoking cessation treatment. The polymorphism status of CHRNA5 might be correlated with shorter survival in Japanese patients with lung cancer25. However, in our study, GG, AG, AA genotypes of CHRNA5 (rs16969968) polymorphisms had no significant difference among the three groups. Similarly, Islam et al. reported that CHRNA5 (rs16969968) had no association with lung cancer risk and smoking status in the Bangladeshi population 26. The reason may be that the lung cancer patients in these studies were different from those of the normal population.
As previously mentioned 27, 28, the same nAchRA3 subunits of the human bronchial epithelium cells were expressed, and the 15q24-25 region of nAchRA3 played an important role in nicotine addiction. In the current study, patients with GG genotypes of CHRNA3 rs578776 polymorphisms had lower nicotine addiction and quit smoking more easily. Additionally, Niu X et al. 29 reported that CHRNA3 was a predictive and prognostic factor in advanced stage
NSCLC in Chinese. SNPs of CHRNA3 and CHRNA5 were associated with resistance to chemotherapeutic drugs in NSCLC cell lines30. Flora et al. reported that the SNPs of rs8023462 were associated with human addition-related phenotypes, which could be potential therapeutic targets31. Forced expression of CHRNA3 was systematically hypermethylated and downregulated in lung cancers and resulted in apoptosis, suggesting that hypermethylation of CHRNA3 played a significant role in sustaining the survival of cancer cells32. It is suggested that China's tobacco control policy-making authorities incorporate the findings into their decision-making. Once lung cancer occurs, patients who carry nicotine-dependent genes may not be able to successfully quit smoking. The impact and interest of tobacco control policy at a population individual level are that doctors can advise patients to test SNPs of CHRNA3 (rs578776) and CHRNA4 (rs1044396 and rs2229959). The test results were used to determine whether they could successfully quit smoking.
The current study is limited by its cross-sectional design. A longitudinal study would be useful to determine the potential psychological parameters after successful smoking cessation in patients with lung cancer. The interaction of bad habits such as alcohol use was not included in the baseline data. Further research evaluating the influence of alcohol consumption smoking cessation should be considered in the future. Due to the limited material and financial resources, a small number of samples have been included in nicotine-dependent gene monitoring, and strictly designed studies with large samples are still needed in the future.